Antiallergic

ABSTRACT

A medicament for the preventive and/or therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:  
                 
wherein X represents a connecting group whose number of atoms in the main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, E represents an aryl group which may be substituted or a hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene which may have one or more substituents in addition to the group represented by formula —O-A wherein A has the same meaning as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.

FIELD OF INVENTION

The present invention relates to pharmaceutical compositions effectivefor preventive and/or therapeutic treatment of allergic diseases such aspollinosis, bronchial asthma, atopic dermatitis, urticaria;endometriosis, and hysteromyoma.

BACKGROUND ART

Allergic diseases are understood to be caused by production of IgE by anantigen stimulation invaded in a body, and successive release of variouschemical mediators such as inflammatory cytokine, histamine, leukotrieneand the like by a degranulation from an activated mast cell stimulatedby a complex of the antigen and IgE, thereby constriction of airway,accentuation of vascular permeability, inflammation of skin, bronchi andthe like are induced. Accordingly, antiallergic agents are understoodmainly as drugs inhibiting allergic reaction type I andsuccessively-induced allergic inflammation, particularly as drugsinhibiting the production and release of the mediators from mast cells,or those as being antagonists against the aforementioned actions. Atpresent, steroids, antihistaminic drugs, suppressants or inhibitors ofthe release of mediators and the like have been used as antiallergicagents. Although steroids are very effective drugs, they have a problemof side effects. Antihistaminic drugs are only for symptomatic therapiesand fail to achieve radical therapy. Suppressants or inhibitors of therelease of mediators are considered to have a high effectiveness.However, some of them lack immediate effectiveness or have central sideeffects. Accordingly, the antiallergic drugs currently available are notfully satisfactory as they are.

Patients with endometriosis are increasing in recent years, andcurrently, 10 to 14% of females are considered to be suffered from thedisease. Endometriosis has been focused as a cause of sterility, as wellas the disease lowers the quality of life of patients with severe painsduring menstruation and coitus. For a treatment of the disease, atherapy by using a hormone drug has been currently applied as a pseudomenopausal therapy. However, the aforementioned therapy induces strongside effects, and it also has a risk of causing osteoporosis during along-term administration. Therefore, at present, a drug or a method fortreatment with safety and high efficacy is not available.

In recent years, it was found that mast cells exist apparently with highdensity in the lesion of endometriosis (American Journal of ReproductiveImmunology (New York: 1998), (Denmark), Vol. 40, No. 4, p. 291-294), andthat mast cells are activated to lead degranulation (Nikkei Medical,2002, No. 415, p. 28; Fertility and Sterility, (USA), 2002, Vol. 78, No.4, p. 782-786). Furthermore, a relation between endometriosis andallergy is strongly suggested, because interstitial hyperplasia, whichis a major step of infiltration and lesion of mast cells, issignificantly inhibited by the administration of a leukotrieneantagonist having antiallergic action to an endometriosis model rat(Nikkei Medical, 2002, No. 415, p. 28; Fertility and Sterility, (USA),2002, Vol. 78, No. 4, p. 782-786).

Therefore, an antiallergic drug, which strongly inhibits activation ofmast cells and can be used as a therapeutic agent for radical treatmentof allergic diseases, is usable as an effective therapeutic agent forendometriosis.

45% of patients with endometriosis are suffered from hysteromyoma, whichsuggests a relation of hysteromyoma and allergy in the same manner asendometriosis. Accordingly, it is highly probable that an antiallergicagent, which can be used as a therapeutic agent for radical treatment ofallergic diseases, is useful as a therapeutic agent for hysteromyoma.

N-phenylsalicylamide derivatives are disclosed as a plant growthinhibitor in the specification of U.S. Pat. No.4,358,443. Asmedicaments, said derivatives are disclosed as anti-inflammatory agentsin the specification of European Patent No. 0,221,211, Japanese PatentUnexamined Publication (KOKAI) No. (Sho)62-99329, and the specificationof U.S. Pat. No. 6,117,859. Furthermore, they are disclosed as NF-κ Binhibitors in the pamphlets of International Publication WO99/65499,International Publication WO02/49632, and International PublicationWO02/076918, and as inhibitors against the production of cytokines inthe pamphlet of International Publication WO02/051397.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide medicaments that enableradical preventive and/or therapeutic treatment of allergy by aninhibition of allergic reactions. To achieve the aforementioned object,the inventors of the present invention conducted various researches onthe antiallergic actions of salicylamide derivatives which are generallybelieved to have low toxicity. As a result, they found thatN-substituted salicylamide derivatives, particularly N-arylsalicylamidederivatives, specifically N-phenylsalicylamide derivatives whereinaniline moiety is substituted in both of 2- and 5-positions or in bothof 3- and 5-positions, and N-thiazol-2-yl-salicylamide derivativeswherein thiazole ring is substituted in both of 4- and 5-positions haveextremely superior activity in inhibitory action against theproliferation of mast cells, inhibitory action against the degranulationfrom mast cells by antigen and IgE stimulation, and inhibitory actionagainst the production of IgE from activated B cells, and that radicalpreventive and/or therapeutic treatment of allergic diseases can beachieved. The inventors also conducted researches on hydroxyarylderivatives which are analogous compounds thereof. The present inventionwas achieved on the basis of these findings.

The present invention thus provides:

-   (1) A medicament for preventive and/or therapeutic treatment of    allergic diseases and/or endometriosis and/or hysteromyoma which    comprises as an active ingredient a substance selected from the    group consisting of a compound represented by the following general    formula (I) and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof:-   wherein X represents a connecting group whose number of atoms in a    main chain is 2 to 5 (said connecting group may be substituted),-   A represents hydrogen atom or acetyl group,-   E represents an aryl group which may be substituted or a heteroaryl    group which may be substituted,-   ring Z represents an arene which may have one or more substituents    in addition to the group represented by formula —O-A wherein A has    the same meaning as that defined above and the group represented by    formula —X-E wherein each of X and E has the same meaning as that    defined above, or a heteroarene which may have one or more    substituents in addition to the group represented by formula —O-A    wherein A has the same meaning as that defined above and the group    represented by formula —X-E wherein each of X and E has the same    meaning as that defined above.

Examples of preferred medicaments provided by the present inventioninclude:

-   (2) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein X is a group selected    from the following connecting group α (said group may be    substituted):-   [Connecting group α] The groups of the following formulas:-   wherein a bond at the left end binds to ring Z and a bond at the    right end binds to E;-   (3) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein X is a group    represented by the following formula (said group may be    substituted):-   wherein a bond at the left end binds to ring Z and a bond at the    right end binds to E;-   (4) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein A is a hydrogen atom;-   (5) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein ring Z is a C₆ to C₁₀    arene which may have one or more substituents in addition to the    group represented by formula —O-A wherein A has the same meaning as    that defined in the general formula (I) and the group represented by    formula —X-E wherein each of X and E has the same meaning as that    defined in the general formula (I), or a 5 to 13-membered    heteroarene which may have one or more substituents in addition to    the group represented by formula —O-A wherein A has the same meaning    as that defined in the general formula (I) and the group represented    by formula —X-E wherein each of X and E has the same meaning as that    defined in the general formula (I);-   (6) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein ring Z is a ring    selected from the following ring group β:-   [Ring Group β] benzene ring, naphthalene ring, thiophene ring,    pyridine ring, indole ring, quinoxaline ring, and carbazole ring-   wherein said ring may have one or more substituents in addition to    the group represented by formula —O-A wherein A has the same meaning    as that defined in the general formula(I) and the group represented    by formula —X-E wherein each of X and E has the same meaning as that    defined in the general formula (I);-   (7) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein ring Z is a benzene    ring which may have one or more substituents in addition to the    group represented by formula —O-A wherein A has the same meaning as    that defined in the general formula (I) and the group represented by    formula —X-E wherein each of X and E has the same meaning as that    defined in the general formula (I);-   (8) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein ring Z is a benzene    ring which is substituted with halogen atom(s) in addition to the    group represented by formula —O-A wherein A has the same meaning as    that defined in the general formula (I) and the group represented by    formula —X-E wherein each of X and E has the same meaning as that    defined in the general formula (I);-   (9) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein ring Z is a    naphthalene ring which may have one or more substituents in addition    to the group represented by formula —O-A wherein A has the same    meaning as that defined in the general formula (I) and the group    represented by formula —X-E wherein each of X and E has the same    meaning as that defined in the general formula (I);-   (10) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein E is a C₆ to C₁₀ aryl    group which may be substituted or a 5 to 13-membered heteroaryl    group which may be substituted;-   (11) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein E is a phenyl group    which may be substituted;-   (12) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein E is    3,5-bis(trifluoromethyl)phenyl group;-   (13) the aforementioned medicament which comprises as an active    ingredient a substance selected from the group consisting of the    compound and a pharmacologically acceptable salt thereof, and a    hydrate thereof and a solvate thereof, wherein E is a 5-membered    heteroaryl group which may be substituted.

From another aspect, the present invention provides use of each of theaforementioned substances for manufacture of the medicament according tothe aforementioned (1) to (13).

The present invention further provides a method for preventive and/ortherapeutic treatment of allergic diseases and/or endometriosis and/orhysteromyoma in a mammal including a human, which comprises the step ofadministering preventively and/or therapeutically effective amount ofthe aforementioned substances to a mammal including a human.

The present invention further provides:

-   (1) a compound represented by the general formula (I-1) or a salt    thereof, or a hydrate thereof or a solvate thereof:-   wherein Z¹ represents 2-hydroxyphenyl group which may be substituted    in the 5-position or 2-acetoxyphenyl group which may be substituted    in the 5-position, and E¹ represents a phenyl group which may be    substituted.

Preferably, provided is:

-   (2) the compound or a salt thereof, or a hydrate thereof or a    solvate thereof, wherein E¹ is 2,5-bis(trifluoromethyl)phenyl group    or 3,5-bis(trifluoromethyl)phenyl group, except that the following    compounds are excluded:-   N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,-   N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,-   N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,-   N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide, and-   N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide.

More preferably, provided is:

-   (3) the compound or a salt thereof, or a hydrate thereof or a    solvate thereof, wherein Z¹ is 2-hydroxyphenyl group which is    substituted with a halogen atom in the 5-position or 2-acetoxyphenyl    group which is substituted with a halogen atom in the 5-position.

Moreover, the present invention provides:

-   (1) a compound represented by the general formula (I-2) or a salt    thereof, or a hydrate thereof or a solvate thereof:-   wherein Z² represents 2-hydroxyphenyl group which may be substituted    in the 5-position or 2-acetoxyphenyl group which may be substituted    in the 5-position, E² represents a 2,5-di-substituted phenyl group    wherein one of said substituents is trifluoromethyl group or a    3,5-di-substituted phenyl group wherein one of said substituents is    trifluoromethyl group, provided that the following compounds are    excluded:-   5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,-   5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,-   5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]-benzamide,-   5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,-   5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide,-   5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,-   5-chloro-2-hydroxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide,    and-   5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.

Preferably, provided is:

-   (2) the compound or a salt thereof, or a hydrate thereof or a    solvate thereof, wherein Z² is 2-hydroxyphenyl group which is    substituted with a halogen atom in the 5-position or 2-acetoxyphenyl    group which is substituted with a halogen atom in the 5-position.

Moreover, the present invention provides:

-   (1) a compound represented by the general formula (I-3) or a salt    thereof, or a hydrate thereof or a solvate thereof:-   wherein Z³ represents 2-hydroxyphenyl group which may be substituted    in the 5-position or 2-acetoxyphenyl group which may be substituted    in the 5-position, E³ represents a group represented by the    following formula:-   wherein one of R^(3e2) and R^(3e3) represents hydrogen atom and the    other represents a hydrocarbon group which may be substituted or    hydroxyl group which may be substituted, and-   R^(3e5) represents a C₂ to C₆ hydrocarbon group which may be    substituted.

Preferably, provided is:

-   (2) the compound according to claim 18 or a salt thereof, or a    hydrate thereof or a solvate thereof, wherein Z³ is 2-hydroxyphenyl    group which is substituted with a halogen atom in the 5-position or    2-acetoxyphenyl group which is substituted with a halogen atom in    the 5-position.

The present invention also provides:

-   (1) a compound represented by the general formula (I-4) or a salt    thereof, or a hydrate thereof or a solvate thereof:-   wherein Z⁴ represents 2-hydroxyphenyl group which may be substituted    in the 5-position or 2-acetoxyphenyl group which may be substituted    in the 5-position, E⁴ represents a group represented by the    following formula:-   wherein R^(4e4) represents a hydrocarbon group which may be    substituted, R^(4e5) represents a halogen atom, cyano group, an acyl    group which may be substituted, or a heterocyclic group which may be    substituted.

Preferably, provided is:

-   (2) the compound or a salt thereof, or a hydrate thereof or a    solvate thereof, wherein Z⁴ is 2-hydroxyphenyl group which is    substituted with a halogen atom in the 5-position or 2-acetoxyphenyl    group which is substituted with a halogen atom in the 5-position.

BRIEF EXPLANATION OF THE DRAWINGS

FIG. 1 shows inhibitory effect of the medicament of the presentinvention (compound No. 50) against immediate type allergy.

FIG. 2 shows inhibitory effect of the medicament of the presentinvention (compound No. 50) against dermatitis with an atopic dermatitismodel.

BEST MODE FOR CARRYING OUT THE INVENTION

Reference to the disclosure of the pamphlet of International PublicationWO02/49632 is useful for better understanding of the present invention.The entire disclosure of the aforementioned pamphlet of InternationalPublication WO02/49632 is incorporated by reference in the disclosuresof the present specification.

The terms used in the present specification have the following meanings.

As the halogen atom, any of fluorine atom, chlorine atom, bromine atom,or iodine atom may be used unless otherwise specifically referred to.

Examples of the hydrocarbon group include, for example, an aliphatichydrocarbon group, an aryl group, an arylene group, an aralkyl group, abridged cyclic hydrocarbon group, a spiro cyclic hydrocarbon group, anda terpene hydrocarbon.

Examples of the aliphatic hydrocarbon group include, for example, alkylgroup, alkenyl group, alkynyl group, alkylene group, alkenylene group,alkylidene group and the like which are straight chain or branched chainmonovalent or bivalent acyclic hydrocarbon groups; cycloalkyl group,cycloalkenyl group, cycloalkanedienyl group, cycloalkyl-alkyl group,cycloalkylene group, and cycloalkenylene group, which are saturated orunsaturated monovalent or bivalent alicyclic hydrocarbon groups.

Examples of the alkyl group include, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, n-octyl, n-nonyl,n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, andn-pentadecyl, which are C₁ to C₁₅ straight chain or branched chain alkylgroups.

Examples of the alkenyl group include, for example, vinyl,prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl,but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl,pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl,3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl,hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl,4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, hept-1-en-1-yl,hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl,non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl,undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl, tridec-1-en-1-yl,tridec-12-en-1-yl, tetradec-1-en-1-yl, tetradec-13-en-1-yl,pentadec-1-en-1-yl, and pentadec-14-en-1-yl, which are C₂ to C₁₅straight chain or branched chain alkenyl groups.

Examples of the alkynyl group include, for example, ethynyl,prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl,1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl,hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl,oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl, dec-1-yn-1-yl,dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl, dodec-1-yn-1-yl,dodec-11-yn-1-yl, tridec-1-yn-1-yl, tridec-12-yn-1-yl,tetradec-1-yn-1-yl, tetradec-13-yn-1-yl, pentadec-1-yn-1-yl, andpentadec-14-yn-1-yl, which are C₂ to C₁₅ straight chain or branchedchain alkynyl groups.

Examples of the alkylene group include, for example, methylene,ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl,propane-2,2-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,and 1,1,4,4-tetramethylbutane-1,4-diyl group, which are C₁ to C₈straight chain or branched chain alkylene groups.

Examples of the alkenylene group include, for example, ethene-1,2-diyl,propene-1,3-diyl, but-1-ene-1,4-diyl, but-2-ene-1,4-diyl,2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl, and hex-3-ene-1,6-diyl,which are C₁ to C₆ straight chain or branched chain alkylene groups.

Examples of the alkylidene group include, for example, methylidene,ethylidene, propylidene, isopropylidene, butylidene, pentylidene, andhexylidene, which are C₁ to C₆ straight chain or branched chainalkylidene groups.

Examples of the cycloalkyl group include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, whichare C₃ to C₈ cycloalkyl groups.

The aforementioned cycloalkyl group may be fused with benzene ring,naphthalene ring and the like, and examples include, for example,1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl, and1,2,3,4-tetrahydronaphthalen-2-yl.

Examples of the cycloalkenyl group include, for example,2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,1-cyclobuten-1-yl, and 1-cyclopenten-1-yl, which are C₃ to C₆cycloalkenyl groups.

The aforementioned cycloalkenyl group may be fused with benzene ring,naphthalene ring and the like, and examples include, for example,1-indanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-1-yl,1,2,3,4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.

Examples of the cycloalkanedienyl group include, for example,2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and2,5-cyclohexanedien-1-yl, which are C₅ to C₆ cycloalkanedienyl groups.

The aforementioned cycloalkanedienyl group may be fused with benzenering, naphthalene ring and the like, and examples include, for example,1-indenyl and 2-indenyl.

Examples of the cycloalkyl-alkyl group include the groups in which onehydrogen atom of the alkyl group is substituted with a cycloalkyl group,and include, for example, cyclopropylmethyl, 1-cyclopropylethyl,2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl,5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl,cyclopentylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl,cyclooctylmethyl, and 6-cyclooctylhexyl, which are C₄ to C₁₄cycloalkyl-alkyl groups.

Examples of the cycloalkylene group include, for example,cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl,cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl,cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl,cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl,cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, andcyclooctane-1,2-diyl, which are C₃ to C₈ cycloalkylene groups.

Examples of the cycloalkenylene group include, for example,2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl,2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl,2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl, 2-cyclohexene-1,4-diyl,3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl,and 1-cyclohexene-1,2-diyl, which are C₃ to C₆ cycloalkenylene groups.

Examples of the aryl group include a monocyclic or a fused polycyclicaromatic hydrocarbon group, and include, for example, phenyl,1-naphthyl, 2-naphthyl, anthryl, phenanthryl, and acenaphthylenyl, whichare C₆ to C₁₄ aryl groups.

The aforementioned aryl group may be fused with the aforementioned C₃ toC₈ cycloalkyl group, C₃ to C₆ cycloalkenyl group, C₅ to C₆cycloalkanedienyl group or the like, and examples include, for example,4-indanyl, 5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl,1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl, 4-acenaphthenyl,inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl, 4-phenalenyl,5-phenalenyl, 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and9-phenalenyl.

Examples of the arylene group include, for example, 1,2-phenylene,1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl,naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl,naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl,naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl,naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl, andanthracene-1,4-diyl, which are C₆ to C₁₄ arylene groups.

Examples of the aralkyl group include the groups in which one hydrogenatom of the alkyl group is substituted with an aryl group, and include,for example, benzyl, 1-naphthylmethyl, 2-naphthylmethyl,anthracenylmethyl, phenanthrenylmethyl, acenaphthylenylmethyl,diphenylmethyl, 1-phenethyl, 2-phenethyl, 1-(1-naphthyl)ethyl,1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl,3-phenylpropyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl,4-phenylbutyl, 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, 5-phenylpentyl,5-(1-naphthyl)pentyl, 5-(2-naphthyl)pentyl, 6-phenylhexyl,6-(1-naphthyl)hexyl, and 6-(2-naphthyl)hexyl, which are C₇ to C₁₆aralkyl groups.

Examples of the bridged cyclic hydrocarbon group include, for example,bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]octyl, andadamantyl.

Examples of the spiro cyclic hydrocarbon group include, for example,spiro[3.4]octyl, and spiro[4.5]deca-1,6-dienyl.

Examples of the terpene hydrocarbon include, for example, geranyl,neryl, linalyl, phytyl, menthyl, and bornyl.

Examples of the halogenated alkyl group include the groups in which onehydrogen atom of the alkyl group is substituted with a halogen atom, andinclude, for example, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,heptafluoropropyl, heptafluoroisopropyl, nonafluorobutyl, andperfluorohexyl, which are C₁ to C₆ straight chain or branched chainhalogenated alkyl groups substituted with 1 to 13 halogen atoms.

Examples of the heterocyclic group include, for example, a monocyclic ora fused polycyclic hetero aryl group which comprises at least one atomof 1 to 3 kinds of hetero atoms selected from oxygen atom, sulfur atom,nitrogen atom and the like as ring-constituting atoms (ring formingatoms), and a monocyclic or a fused polycyclic non-aromatic heterocyclicgroup which comprises at least one atom of 1 to 3 kinds of hetero atomsselected from oxygen atom, sulfur atom, nitrogen atom and the like asring-constituting atoms (ring forming atoms).

Examples of the monocyclic heteroaryl group include, for example,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, (1,2,3-oxadiazol)-4-yl,(1,2,3-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl,(1,2,5-oxadiazol)-3-yl, (1,2,5-oxadiazol)-4-yl, (1,3,4-oxadiazol)-2-yl,(1,3,4-oxadiazol)-5-yl, furazanyl, (1,2,3-thiadiazol)-4-yl,(1,2,3-thiadiazol)-5-yl, (1,2,4-thiadiazol)-3-yl,(1,2,4-thiadiazol)-5-yl, (1,2,5-thiadiazol)-3-yl,(1,2,5-thiadiazol)-4-yl, (1,3,4-thiadiazolyl)-2-yl,(1,3,4-thiadiazolyl)-5-yl, (1H-1,2,3-triazol)-1-yl,(1H-1,2,3-triazol)-4-yl, (1H-1,2,3-triazol)-5-yl,(2H-1,2,3-triazol)-2-yl, (2H-1,2,3-triazol)-4-yl,(1H-1,2,4-triazol)-1-yl, (1H-1,2,4-triazol)-3-yl,(1H-1,2,4-triazol)-5-yl, (4H-1,2,4-triazol)-3-yl,(4H-1,2,4-triazol)-4-yl, (1H-tetrazol)-1-yl, (1H-tetrazol)-5-yl,(2H-tetrazol)-2-yl, (2H-tetrazol)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl, (1,2,3-triazin)-4-yl, (1,2,3-triazin)-5-yl,(1,2,4-triazin)-3-yl, (1,2,4-triazin)-5-yl, (1,2,4-triazin)-6-yl,(1,3,5-triazin)-2-yl, 1-azepinyl, 2-azepinyl, 3-azepinyl, 4-azepinyl,(1,4-oxazepin)-2-yl, (1,4-oxazepin)-3-yl, (1,4-oxazepin)-5-yl,(1,4-oxazepin)-6-yl, (1,4-oxazepin)-7-yl, (1,4-thiazepin)-2-yl,(1,4-thiazepin)-3-yl, (1,4-thiazepin)-5-yl, (1,4-thiazepin)-6-yl, and(1,4-thiazepin)-7-yl, which are 5 to 7-membered monocyclic heteroarylgroups.

Examples of the fused polycyclic heteroaryl group include, for example,2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl,6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl,5-isobenzofuranyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl,7-benzo[b]thienyl, 1-benzo[c]thienyl, 4-benzo[c]thienyl,5-benzo[c]thienyl, 1-indolyl, 1-indolyl, 2-indolyl, 3-indolyl,4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindol)-1-yl,(2H-isoindol)-2-yl, (2H-isoindol)-4-yl, (2H-isoindol)-5-yl,(1H-indazol)-1-yl, (1H-indazol)-3-yl, (1H-indazol)-4-yl,(1H-indazol)-5-yl, (1H-indazol)-6-yl, (1H-indazol)-7-yl,(2H-indazol)-1-yl, (2H-indazol)-2-yl, (2H-indazol)-4-yl,(2H-indazol)-5-yl, 2-benzoxazolyl, 2-benzoxazolyl, 4-benzoxazolyl,5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl, (1,2-benzisoxazol)-3-yl,(1,2-benzisoxazol)-4-yl, (1,2-benzisoxazol)-5-yl,(1,2-benzisoxazol)-6-yl, (1,2-benzisoxazol)-7-yl,(2,1-benzisoxazol)-3-yl, (2,1-benzisoxazol)-4-yl,(2,1-benzisoxazol)-5-yl, (2,1-benzisoxazol)-6-yl,(2,1-benzisoxazol)-7-yl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl,(1,2-benzisothiazol)-3-yl, (1,2-benzisothiazol)-4-yl,(1,2-benzisothiazol)-5-yl, (1,2-benzisothiazol)-6-yl,(1,2-benzisothiazol)-7-yl, (2,1-benzisothiazol)-3-yl,(2,1-benzisothiazol)-4-yl, (2,1-benzisothiazol)-5-yl,(2,1-benzisothiazol)-6-yl, (2,1-benzisothiazol)-7-yl,(1,2,3-benzoxadiazol)-4-yl, (1,2,3-benzoxadiazol)-5-yl,(1,2,3-benzoxadiazol)-6-yl, (1,2,3-benzoxadiazol)-7-yl,(2,1,3-benzoxadiazol)-4-yl, (2,1,3-benzoxadiazol)-5-yl,(1,2,3-benzothiadiazol)-4-yl, (1,2,3-benzothiadiazol)-5-yl,(1,2,3-benzothiadiazol)-6-yl, (1,2,3-benzothiadiazol)-7-yl,(2,1,3-benzothiadiazol)-4-yl, (2,1,3-benzothiadiazol)-5-yl,(1H-benzotriazol)-1-yl, (1H-benzotriazol)-4-yl, (1H-benzotriazol)-5-yl,(1H-benzotriazol)-6-yl, (1H-benzotriazol)-7-yl, (2H-benzotriazol)-2-yl,(2H-benzotriazol)-4-yl, (2H-benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl,5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-quinazolinyl,4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl,1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 2-naphthyridinyl,3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl, 6-purinyl, 7-purinyl,8-purinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl,1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, 9-carbazolyl,2-(α-carbolinyl), 3-(α-carbolinyl), 4-(α-carbolinyl), 5-(α-carbolinyl),6-(α-carbolinyl), 7-(α-carbolinyl), 8-(α-carbolinyl), 9-(α-carbolinyl),1-(β-carbolinyl), 3-(β-carbolinyl), 4-(β-carbolinyl), 5-(β-carbolinyl),6-(β-carbolinyl), 7-(β-carbolinyl), 8-(β-carbolinyl), 9-(β-carbolinyl),1-(γ-carbolinyl), 2-(γ-carbolinyl), 4-(γ-carbolinyl), 5-(γ-carbolinyl),6-(γ-carbolinyl), 7-(γ-carbolinyl), 8-(γ-carbolinyl), 9-(γ-carbolinyl),1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl,1-phenoxazinyl, 2-phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl,10-phenoxazinyl, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl,4-phenothiazinyl, 10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl,1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl,4-phenanthridinyl, 6-phenanthridinyl, 7-phenanthridinyl,8-phenanthridinyl, 9-phenanthridinyl, 10-phenanthridinyl,2-phenanthrolinyl, 3-phenanthrolinyl, 4-phenanthrolinyl,5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl,8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl,1-thianthrenyl, 2-thianthrenyl, 1-indolizinyl, 2-indolizinyl,3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl,8-indolizinyl, 1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl,4-phenoxathiinyl, thieno[2,3-b]furyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[11,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-a]pyridazinyl,which are 8 to 14-membered fused polycyclic heteroaryl groups.

Examples of the monocyclic non-aromatic heterocyclic group include, forexample, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl,1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl),2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl), piperidino,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-homopiperidinyl,2-tetrahydropyranyl, morpholino, (thiomorpholin)-4-yl, 1-piperazinyl,and 1-homopiperazinyl, which are 3 to 7-membered saturated orunsaturated monocyclic non-aromatic heterocyclic groups.

Examples of the fused polycyclic non-aromatic heterocyclic groupinclude, for example, 2-quinuclidinyl, 2-chromanyl, 3-chromanyl,4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl,1-isochromanyl, 3-isochromanyl, 4-isochromanyl, 5-isochromanyl,6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 2-thiochromanyl,3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl,7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl,3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochromanyl,6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochromanyl, 1-indolinyl,2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl,7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl,5-isoindolinyl, 2-(4H-chromenyl), 3-(4H-chromenyl), 4-(4H-chromenyl),5-(4H-chromenyl), 6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl),1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl,6-isochromenyl, 7-isochromenyl, 8-isochromenyl, 1-(1H-pyrrolidinyl),2-(1H-pyrrolidinyl), 3-(1H-pyrrolidinyl), 5-(1H-pyrrolidinyl),6-(1H-pyrrolidinyl), and 7-(1H-pyrrolidinyl), which are 8 to 10-memberedsaturated or unsaturated fused polycyclic non-aromatic heterocyclicgroups.

Among the aforementioned heterocyclic groups, a monocyclic or a fusedpolycyclic hetero aryl groups which may have 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and thelike, in addition to the nitrogen atom that has the bond, asring-constituting atoms (ring forming atoms), and a monocyclic or afused polycyclic non-aromatic heterocyclic groups which may have 1 to 3kinds of hetero atoms selected from oxygen atom, sulfur atom, nitrogenatom and the like, in addition to the nitrogen atom that has the bond,as ring-constituting atoms (ring forming atoms) are referred to as“cyclic amino group.” Examples include, for example, 1-pyrrolidinyl,1-imidazolidinyl, 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl,piperidino, morpholino, 1-piperazinyl, thiomorpholin-4-yl,1-homopiperidinyl, 1-homopiperazinyl, 2-pyrolin-1-yl, 2-imidazolin-1-yl,2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl,1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-indolyl, 1-indazolyl, and2-isoindolyl.

The aforementioned cycloalkyl group, cycloalkenyl group,cycloalkanedienyl group, aryl group, cycloalkylene group,cycloalkenylene group, arylene group, bridged cyclic hydrocarbon group,spiro cyclic hydrocarbon group, and heterocyclic group are genericallyreferred to as “cyclic group.” Furthermore, among said cyclic groups,particularly, aryl group, arylene group, monocyclic heteroaryl group,and fused polycyclic heteroaryl group are generically referred to as“aromatic ring group.”

Examples of the hydrocarbon-oxy group include the groups in which ahydrogen atom of the hydroxy group is substituted with a hydrocarbongroup, and examples of the hydrocarbon include similar groups to theaforementioned hydrocarbon groups. Examples of the hydrocarbon-oxy groupinclude, for example, alkoxy group (alkyl-oxy group), alkenyl-oxy group,alkynyl-oxy group, cycloalkyl-oxy group, cycloalkyl-alkyl-oxy group andthe like, which are aliphatic hydrocarbon-oxy groups; aryl-oxy group;aralkyl-oxy group; and alkylene-dioxy group.

Examples of the alkoxy (alkyl-oxy group) include, for example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1-methylbutoxy,neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy,4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethybutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy,1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nonyloxy,n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n-tetradecyloxy,and n-pentadecyloxy, which are C₁ to C₁₅ straight chain or branchedchain alkoxy groups.

Examples of the alkenyl-oxy group include, for example, vinyloxy,(prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, (but-1-en-1-yl)oxy,(but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, (2-methylprop-2-en-1-yl)oxy,(1-methylprop-2-en-1-yl)oxy, (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy,(pent-3-en-1-yl)oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy,(3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy,(hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy,(4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy,(hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1-en-1-yl)oxy,(oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8-en-1-yl)oxy,(dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec-1-en-1-yl)oxy,(undec-10-en-1-yl)oxy, (dodec-1-en-1-yl)oxy, (dodec-11-en-1-yl)oxy,(tridec-1-en-1-yl)oxy, (tridec-12-en-1-yl)oxy, (tetradec-1-en-1-yl)oxy,(tetradec-13-en-1-yl)oxy, (pentadec-1-en-1-yl)oxy, and(pentadec-14-en-1-yl)oxy, which are C₂ to C₁₅ straight chain or branchedchain alkenyl-oxy groups.

Examples of the alkynyl-oxy group include, for example, ethynyloxy,(prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but-1-yn-1-yl)oxy,(but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy,(pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy,(hept-1-yn-1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy,(oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy,(dec-1-yn-1-yl)oxy, (dec-9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy,(undec-10-yn-1-yl)oxy, (dodec-1-yn-1-yl)oxy, (dodec-11-yn-1-yl)oxy,(tridec-1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy, (tetradec-1-yn-1-yl)oxy,(tetradec-13-yn-1-yl)oxy, (pentadec-1-yn-1-yl)oxy, and(pentadec-14-yn-1-yl)oxy, which are C₂ to C₁₅ straight chain or branchedchain alkynyl-oxy groups.

Examples of the cycloalkyl-oxy group include, for example, cyclopropoxy,cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, andcyclooctyloxy, which are C₃ to C₈ cycloalkyl-oxy groups.

Examples of the cycloalkyl-alkyl-oxy group include, for example,cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy,3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy,6-cyclopropylhexyloxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy,cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctylhexyloxy, whichare C₄ to C₁₄ cycloalkyl-alkyl-oxy groups.

Examples of the aryl-oxy group include, for example, phenoxy,1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy, andacenaphthylenyloxy, which are C₆ to C₁₄ aryl-oxy groups.

Examples of the aralkyl-oxy group include, for example, benzyloxy,1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy,phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy,1-phenethyloxy, 2-phenethyloxy, 1-(1-naphthyl)ethoxy,1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy, 2-(2-naphthyl)ethoxy,3-phenylpropoxy, 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy,4-phenylbutoxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy,5-phenylpentyloxy, 5-(1-naphthyl)pentyloxy, 5-(2-naphthyl)pentyloxy,6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy, and 6-(2-naphthyl)hexyloxy,which are C₇ to C₁₆ aralkyl-oxy groups.

Examples of the alkylenedioxy group include, for example,methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and1,1-dimethylmethylenedioxy.

Examples of the halogenated alkoxy group (halogenated alkyl-oxy group)include the groups in which a hydrogen atom of the hydroxy group issubstituted with a halogenated alkyl group, and include, for example,fluoromethoxy, difluoromethoxy, chloromethoxy, bromomethoxy,iodomethoxy, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy,heptafluoroisopropoxy, nonafluorobutoxy, and perfluorohexyloxy, whichare C₁ to C₆ straight chain or branched chain halogenated alkoxy groupssubstituted with 1 to 13 halogen atoms.

Examples of the heterocyclic-oxy group include the groups in which ahydrogen atom of the hydroxy group is substituted with a heterocyclicgroup, and examples of the heterocyclic ring include similar groups tothe aforementioned heterocyclic groups. Examples of the heterocyclic-oxygroup include, for example, a monocyclic heteroaryl-oxy group, a fusedpolycyclic heteroaryl-oxy group, a monocyclic non-aromaticheterocyclic-oxy group, and a fused polycyclic non-aromaticheterocyclic-oxy group.

Examples of the monocyclic heteroaryl-oxy group include, for example,3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy, 2-pyridyloxy,3-pyridyloxy, 4-pyridyloxy, and (pyrimidin-4-yl)oxy.

Examples of the fused polycyclic heteroaryl-oxy group include, forexample, 5-indolyloxy, (benzimidazol-2-yl)oxy, 2-quinolyloxy,3-quinolyloxy, and 4-quinolyloxy.

Examples of the monocyclic non-aromatic heterocyclic-oxy group include,for example, 3-pyrrolidinyloxy, and 4-piperidinyloxy.

Examples of the fused polycyclic non-aromatic heterocyclic-oxy groupinclude, for example, 3-indolynyloxy, and 4-chromanyloxy.

Examples of the hydrocarbon-sulfanyl group include the groups in which ahydrogen atom of the sulfanyl group is substituted with a hydrocarbongroup, and examples of the hydrocarbon include similar groups to theaforementioned hydrocarbon groups. Examples of the hydrocarbon-sulfanylgroups include, for example, alkyl-sulfanyl group, alkenyl-sulfanylgroup, alkynyl-sulfanyl group, cycloalkyl-sulfanyl group,cycloalkyl-alkyl-sulfanyl group and the like, which are aliphatichydrocarbon-sulfanyl groups; aryl-sulfanyl group, and aralkyl-sulfanylgroup.

Examples of the alkyl-sulfanyl group include, for example,methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl,n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl,tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl,(2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl, neopentylsulfanyl,(1,2-dimethylpropyl)sulfanyl, (1-ethylpropyl)sulfanyl, n-hexylsulfanyl,(4-methylpentyl)sulfanyl, (3-methylpentyl)sulfanyl,(2-methylpentyl)sulfanyl, (1-methylpentyl)sulfanyl,(3,3-dimethylbutyl)sulfanyl, (2,2-dimethylbutyl)sulfanyl,(1,1-dimethylbutyl)sulfanyl, (1,2-dimethylbutyl)sulfanyl,(1,3-dimethylbutyl)sulfanyl, (2,3-dimethylbutyl)sulfanyl,(2-ethylbutyl)sulfanyl, (1-ethylbutyl)sulfanyl,(1-ethyl-1-methylpropyl)sulfanyl, n-heptylsulfanyl, n-octylsulfanyl,n-nonylsulfanyl, n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl,n-tridecylsulfanyl, n-tetradecylsulfanyl, and n-pentadecylsulfanyl,which are C₁ to C₁₅ straight chain or branched chain alkyl-sulfanylgroups.

Examples of the alkenyl-sulfanyl group include, for example,vinylsulfanyl, (prop-1-en-1-yl)sulfanyl, allylsulfanyl,isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl, (but-2-en-1-yl)sulfanyl,(but-3-en-1-yl)sulfanyl, (2-methylprop-2-en-1-yl)sulfanyl,(1-methylprop-2-en-1-yl)sulfanyl, (pent-1-en-1-yl)sulfanyl,(pent-2-en-1-yl)sulfanyl, (pent-3-en-1-yl)sulfanyl,(pent-4-en-1-yl)sulfanyl, (3-methylbut-2-en-1-yl)sulfanyl,(3-methylbut-3-en-1-yl)sulfanyl, (hex-1-en-1-yl)sulfanyl,(hex-2-en-1-yl)sulfanyl, (hex-3-en-1-yl)sulfanyl,(hex-4-en-1-yl)sulfanyl, (hex-5-en-1-yl)sulfanyl,(4-methylpent-3-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl,(hept-1-en-1-yl)sulfanyl, (hept-6-en-1-yl)sulfanyl,(oct-1-en-1-yl)sulfanyl, (oct-7-en-1-yl)sulfanyl,(non-1-en-1-yl)sulfanyl, (non-8-en-1-yl)sulfanyl,(dec-1-en-1-yl)sulfanyl, (dec-9-en-1-yl)sulfanyl,(undec-1-en-1-yl)sulfanyl, (undec-10-en-1-yl)sulfanyl,(dodec-1-en-1-yl)sulfanyl, (dodec-11-en-1-yl)sulfanyl,(tridec-1-en-1-yl)sulfanyl, (tridec-12-en-1-yl)sulfanyl,(tetradec-1-en-1-yl)sulfanyl, (tetradec-13-en-1-yl)sulfanyl,(pentadec-1-en-1-yl)sulfanyl, and (pentadec-14-en-1-yl)sulfanyl, whichare C₂ to C₁₅ straight chain or branched chain alkenyl-sulfanyl groups.

Examples of the alkynyl-sulfanyl group include, for example,ethynylsulfanyl, (prop-1-yn-1-yl)sulfanyl, (prop-2-yn-1-yl)sulfanyl,(but-1-yn-1-yl)sulfanyl, (but-3-yn-1-yl)sulfanyl,(1-methylprop-2-yn-1-yl)sulfanyl, (pent-1-yn-1-yl)sulfanyl,(pent-4-yn-1-yl)sulfanyl, (hex-1-yn-1-yl)sulfanyl,(hex-5-yn-1-yl)sulfanyl, (hept-1-yn-1-yl)sulfanyl,(hept-6-yn-1-yl)sulfanyl, (oct-1-yn-1-yl)sulfanyl,(oct-7-yn-1-yl)sulfanyl, (non-1-yn-1-yl)sulfanyl,(non-8-yn-1-yl)sulfanyl, (dec-1-yn-1-yl)sulfanyl,(dec-9-yn-1-yl)sulfanyl, (undec-1-yn-1-yl)sulfanyl,(undec-10-yn-1-yl)sulfanyl, (dodec-1-yn-1-yl)sulfanyl,(dodec-11-yn-1-yl)sulfanyl, (tridec-1-yn-1-yl)sulfanyl,(tridec-12-yn-1-yl)sulfanyl, (tetradec-1-yn-1-yl)sulfanyl,(tetradec-13-yn-1-yl)sulfanyl, (pentadec-1-yn-1-yl)sulfanyl, and(pentadec-14-yn-1-yl)sulfanyl, which are C₂ to C₁₅ straight chain orbranched chain alkynyl-sulfanyl groups.

Examples of the cycloalkyl-sulfanyl group include, for example,cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl,cyclohexylsulfanyl, cycloheptylsulfanyl, and cyclooctylsulfanyl, whichare C₃ to C₈ cycloalkyl-sulfanyl groups.

Examples of the cycloalkyl-alkyl-sulfanyl group include, for example,(cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl,(2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl,(4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl,(6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl,(cyclopentylmethyl)sulfanyl, (cyclobutylmethyl)sulfanyl,(cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl,(2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl,(4-cyclohexylbutyl)sulfanyl, (cycloheptylmethyl)sulfanyl,(cyclooctylmethyl)sulfanyl, and (6-cyclooctylhexyl)sulfanyl, which areC₄ to C₁₄ cycloalkyl-alkyl-sulfanyl groups.

Examples of the aryl-sulfanyl group include, for example,phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl, anthrylsulfanyl,fenanthrylsulfanyl, and acenaphthylenylsulfanyl, which are C₆ to C₁₄aryl-sulfanyl groups.

Examples of the aralkyl-sulfanyl group include, for example,benzylsulfanyl, (1-naphthylmethyl)sulfanyl, (2-naphthylmethyl)sulfanyl,(anthracenylmethyl)sulfanyl, (phenanthrenylmethyl)sulfanyl,(acenaphthylenylmethyl)sulfanyl, (diphenylmethyl)sulfanyl,(1-phenethyl)sulfanyl, (2-phenethyl)sulfanyl,(1-(1-naphthyl)ethyl)sulfanyl, (1-(2-naphthyl)ethyl)sulfanyl,(2-(1-naphthyl)ehyl)sulfanyl, (2-(2-naphthyl)ethyl)sulfanyl,(3-phenylpropyl)sulfanyl, (3-(1-naphthyl)propyl)sulfanyl,(3-(2-naphthyl)propyl)sulfanyl, (4-phenylbutyl)sulfanyl,(4-(1-naphthyl)butyl)sulfanyl, (4-(2-naphthyl)butyl)sulfanyl,(5-phenylpentyl)sulfanyl, (5-(1-naphthyl)pentyl)sulfanyl,(5-(2-naphthyl)pentyl)sulfanyl, (6-phenylhexyl)sulfanyl,(6-(1-naphthyl)hexyl)sulfanyl, and (6-(2-naphthyl)hexyl)sulfanyl, whichare C₇ to C₁₆ aralkyl-sulfanyl groups.

Examples of the halogenated alkyl-sulfanyl group include the groups inwhich a hydrogen atom of the sulfanyl group is substituted with ahalogenated alkyl group, and include, for example,(fluoromethyl)sulfanyl, (chloromethyl)sulfanyl, (bromomethyl)sulfanyl,(iodomethyl)sulfanyl, (difluoromethyl)sulfanyl,(trifluoromethyl)sulfanyl, (trichloromethyl)sulfanyl,(2,2,2-trifluoroethyl)sulfanyl, (pentafluoroethyl)sulfanyl,(3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl)sulfanyl,(heptafluoroisopropyl)sulfanyl, (nonafluorobutyl)sulfanyl, and(perfluorohexyl)sulfanyl, which are C₁ to C₆ straight chain or branchedchain halogenated alkyl-sulfanyl groups substituted with 1 to 13 halogenatoms.

Examples of the heterocyclic-sulfanyl group include the groups in whicha hydrogen atom of the sulfanyl group is substituted with a heterocyclicgroup, and examples of the heterocyclic ring include similar groups tothe aforementioned heterocyclic groups. Examples of theheterocyclic-sulfanyl group include, for example, a monocyclicheteroaryl-sulfanyl group, a fused polycyclic heteroaryl-sulfanyl group,a monocyclic non-aromatic heterocyclic-sulfanyl group, and a fusedpolycyclic non-aromatic heterocyclic-sulfanyl group.

Examples of the monocyclic heteroaryl-sulfanyl group include, forexample, (imidazol-2-yl)sulfanyl, (1,2,4-triazol-2-yl)sulfanyl,(pyridin-2-yl)sulfanyl, (pyridin-4-yl)sulfanyl, and(pyrimidin-2-yl)sulfanyl.

Examples of the fused polycyclic heteroaryl-sulfanyl group include, forexample, (benzimidazol-2-yl)sulfanyl, (quinolin-2-yl)sulfanyl, and(quinolin-4-yl)sulfanyl.

Examples of the monocyclic non-aromatic heterocyclic-sulfanyl groupsinclude, for example, (3-pyrrolidinyl)sulfanyl, and(4-piperidinyl)sulfanyl.

Examples of the fused polycyclic non-aromatic heterocyclic-sulfanylgroup include, for example, (3-indolinyl)sulfanyl, and(4-chromanyl)sulfanyl.

Examples of the acyl group include, for example, formyl group,glyoxyloyl group, thioformyl group, carbamoyl group, thiocarbamoylgroup, sulfamoyl group, sulfinamoyl group, carboxy group, sulfo group,phosphono group, and groups represented by the following formulas:

-   wherein R^(a1) and R^(b1) may be the same or different and represent    a hydrocarbon group or a heterocyclic group, or R^(a1) and R^(b1)    combine to each other, together with the nitrogen atom to which they    bind, to form a cyclic amino group.

In the definition of the aforementioned acyl group, among the groupsrepresented by the formula (ω-1A), those groups in which R^(a1) is ahydrocarbon group are referred to as “hydrocarbon-carbonyl group” whoseexamples include, for example, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, lauroyl, myristoryl, palmitoyl, acryloyl,propioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, andphenylacetyl, and those groups in which R^(a1) is a heterocyclic groupare referred to as “heterocyclic ring-carbonyl group” whose examplesinclude, for example, 2-thenoyl, 3-furoyl, nicotinoyl, andisonicotinoyl.

Among the groups represented by the formula (ω-2A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl group” whose examples include, for example,methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl,and those groups in which R^(a1) is a heterocyclic group are referred toas “heterocyclic ring-oxy-carbonyl group” whose examples include, forexample, 3-pyridyloxycarbonyl.

Among the groups represented by the formula (ω-3A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl group” whose examples include, forexample, pyruvoyl, and those groups in which R^(a1) is a heterocyclicgroup are referred to as “heterocyclic ring-carbonyl-carbonyl group.”

Among the groups represented by the formula (ω-4A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl group” whose examples include, forexample, methoxalyl and ethoxalyl groups, and those groups in whichR^(a1) is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-carbonyl group.”

Among the groups represented by the formula (ω-5A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl group,” and those groups in which R^(a1)is a heterocyclic group are referred to as “heterocyclicring-sulfanyl-carbonyl group.”

Among the groups represented by the formula (ω-6A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-thiocarbonylgroup.”

Among the groups represented by the formula (ω-7A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl group,” and those groups in which R^(a1)is a heterocyclic group are referred to as “heterocyclicring-oxy-thiocarbonyl group.”

Among the groups represented by the formula (ω-8A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl group,” and those groups in whichR^(a1) is a heterocyclic group are referred to as

-   “heterocyclic ring-sulfanyl-thiocarbonyl group.”

Among the groups represented by the formula (ω-9A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as referred to as“N-hydrocarbon-carbamoyl group” whose examples include, for example,N-methylcarbamoyl group, and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-carbamoylgroup.”

Among the groups represented by the formula (ω-10A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-carbamoyl group” whose examples include, for    example, N,N-dimethylcarbamoyl group, those groups in which both    R^(a1) and R^(b1) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-carbamoyl group,” those groups in which    R^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group are    referred to as p0 “N-hydrocarbon-N-heterocyclic ring-substituted    carbamoyl group,” and those groups in which R^(a1) and R^(b1)    combine to each other, together with the nitrogen atom to which they    bind, to form a cyclic amino group are referred to as “cyclic    amino-carbonyl group” whose examples include, for example,    morpholino-carbonyl.

Among the groups represented by the formula (ω-11A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl group,” and those groups in which R^(a1) isa heterocyclic group are referred to as “N-heterocyclicring-thiocarbamoyl group.”

Among the groups represented by the formula (ω-12A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-thiocarbamoyl group,” those groups in which    both R^(a1) and R^(b1) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-thiocarbamoyl group,” those groups in    which R^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-thiocarbamoyl group,” and those groups in which R^(a1) and    R^(b1) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-thiocarbonyl group.”

Among the groups represented by the formula (ω-13A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-sulfamoylgroup.”

Among the groups represented by the formula (ω-14A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfamoyl group” whose examples include, for    example, N,N-dimethylsulfamoyl group, those groups in which both    R^(a1) and R^(b1) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfamoyl group,” those groups in which    R^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group are    referred to as “N-hydrocarbon-N-heterocyclic ring-sulfamoyl group,”    and those groups in which R^(a1) and R^(b1) combine to each other,    together with the nitrogen atom to which they bind, to form a cyclic    amino group are referred to as “cyclic amino-sulfonyl group” whose    examples include, for example 1-pyrrolylsulfonyl.

Among the groups represented by the formula (ω-15A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “N-heterocyclic ring-sulfinamoylgroup.”

Among the groups represented by the formula (ω-16A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfinamoyl group,” those groups in which both    R^(a1) and R^(b1) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfinamoyl group,” those groups in which    R^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic group are    referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl    group,” and those groups in which R^(a1) and R^(b1) combine to each    other, together with the nitrogen atom to which they bind, to form a    cyclic amino group are referred to as “cyclic amino-sulfinyl group.”

Among the groups represented by the formula (ω-17A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-oxy-sulfonylgroup.”

Among the groups represented by the formula (ω-18A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl group,” and those groups in which R^(a1) is aheterocyclic group are referred to as “heterocyclic ring-oxy-sulfinylgroup.”

Among the groups represented by the formula (ω-19A), those groups inwhich both R^(a1) and R^(b1) are hydrocarbon groups are referred to as

-   “O,O′-di(hydrocarbon)-phosphono group,” those groups in which both    R^(a1) and R^(b1) are heterocyclic groups are referred to as    “O,O′-di(heterocyclic ring)-phosphono group,” and those groups in    which R^(a1) is a hydrocarbon group and R^(b1) is a heterocyclic    group are referred to as “O-hydrocarbon-O′-heterocyclic    ring-phosphono group.”

Among the groups represented by the formula (ω-20A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl group” whose examples include, for example,methanesulfonyl and benzenesulfonyl, and those groups in which R^(a1) isa heterocyclic group are referred to as “heterocyclic ring-sulfonylgroup.”

Among the groups represented by the formula (ω-21A), those groups inwhich R^(a1) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl group” whose examples include, for example,methylsulfinyl and benzenesulfinyl, and those groups in which R^(a1) isa heterocyclic group are referred to as “heterocyclic ring-sulfinylgroup.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1A) through (ω-21A) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl group represented by the formula (ω-1A) include,for example, an alkyl-carbonyl group, an alkenyl-carbonyl group, analkynyl-carbonyl group, a cycloalkyl-carbonyl group, acycloalkenyl-carbonyl group, a cycloalkanedienyl-carbonyl group, acycloalkyl-alkyl-carbonyl group, which are aliphatichydrocarbon-carbonyl groups; an aryl-carbonyl group; an aralkyl-carbonylgroup; a bridged cyclic hydrocarbon-carbonyl group; a spirocyclichydrocarbon-carbonyl group; and a terpene family hydrocarbon-carbonylgroup. In the following, groups represented by the formulas (ω-2A)through (ω-21A) are similar to those explained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1A) through (ω-21A) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl group represented by the formula (ω-1A) include, forexample, a monocyclic heteroaryl-carbonyl group, a fused polycyclicheteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclicring-carbonyl group, and a fused polycyclic non-aromatic heterocyclicring-carbonyl group. In the following, groups represented by theformulas (ω-2A) through (ω-21A) are similar to those explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10A) through (ω-16A) include similar groupsto the aforementioned cyclic amino group.

In the present specification, when a certain functional group is definedas “which may be substituted,” the definition means that the functionalgroup may sometimes have one or more substituents at chemicallysubstitutable positions, unless otherwise specifically mentioned. Kindof substituents, number of substituents, and the position ofsubstituents existing in the functional groups are not particularlylimited, and when two or more substituents exist, they may be the sameor different. Examples of the substituent existing in the functionalgroup include, for example, halogen atoms, oxo group, thioxo group,nitro group, nitroso group, cyano group, isocyano group, cyanato group,thiocyanato group, isocyanato group, isothiocyanato group, hydroxygroup, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalogroup, methooxalo group, thiocarboxy group, dithiocarboxy group,carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group,sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group,phosphono group, hydroxyphosphonyl group, hydrocarbon group,heterocyclic group, hydrocarbon-oxy group, heterocyclic ring-oxy group,hydrocarbon-sulfanyl group, heterocyclic ring-sulfanyl group, acylgroup, amino group, hydrazino group, hydrazono group, diazenyl group,ureido group, thioureido group, guanidino group, carbamoimidoyl group(amidino group), azido group, imino group, hydroxyamino group,hydroxyimino group, aminooxy group, diazo group, semicarbazino group,semicarbazono group, allophanyl group, hydantoyl group, phosphano group,phosphoroso group, phospho group, boryl group, silyl group, stannylgroup, selanyl group, oxido group and the like.

When two or more substituents exist according to the aforementioneddefinition of “which may be substituted,” said two or more substituentsmay combine to each other, together with atom(s) to which they bind, toform a ring. For these cyclic groups, as ring-constituting atoms (ringforming atoms), one to three kinds of one or more hetero atoms selectedfrom oxygen atom, sulfur atom, nitrogen atom and the like may beincluded, and one or more substituents may exist on the ring. The ringmay be monocyclic or fused polycyclic, and aromatic or non-aromatic.

The above substituents according to the aforementioned definition of“which may be substituted” may further be substituted with theaforementioned substituents at the chemically substitutable positions onthe substituent. Kind of substituents, number of substituents, andpositions of substituents are not particularly limited, and when thesubstituents are substituted with two or more substituents, they may bethe same or different. Examples of the substituent include, for example,a halogenated alkyl-carbonyl group whose examples include, for example,trifluoroacetyl, a halogenated alkyl-sulfonyl group whose examplesinclude, for example, trifluoromethanesulfonyl, an acyl-oxy group, anacyl-sulfanyl group, an N-hydrocarbon-amino group, anN,N-di(hydrocarbon)-amino group, an N-heterocyclic ring-amino group, anN-hydrocarbon-N-heterocyclic ring-amino group, an acyl-amino group, anda di(acyl)-amino group. Moreover, substitution on the aforementionedsubstituents may be repeated multiple orders.

Examples of the acyl-oxy group include the groups in which hydrogen atomof hydroxy group is substituted with acyl group, and include, forexample, formyloxy group, glyoxyloyloxy group, thioformyloxy group,carbamoloxy group, thiocarbamoyloxy group, sulfamoyloxy group,sulfinamoloxy group, carboxyoxy group, sulphooxy group, phosphonooxygroup, and groups represented by the following formulas:

-   wherein R^(a2) and R^(b2) may be the same or different and represent    a hydrocarbon group or a heterocyclic group, or R^(a2) and R^(b2)    combine to each other, together with the nitrogen atom to which they    bind, to form a cyclic amino group.

In the definition of the aforementioned acyl-oxy group, among the groupsrepresented by the formula (ω-1B), those groups in which R^(a2) is ahydrocarbon group are referred to as “hydrocarbon-carbonyl-oxy group”whose examples include, for example, acetoxy and benzoyloxy, and thosegroups in which R^(a2) is a heterocyclic group are referred to as“heterocyclic ring-carbonyl-oxy group.”

Among the groups represented by the formula (ω-2B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-oxy group,” and those groups in which R^(a2)is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-oxy group.”

Among the groups represented by the formula (ω-3B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as

-   “heterocyclic ring-carbonyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-4B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-carbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-carbonyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-5B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-oxy group,” and those groups where R^(a2)is a heterocyclic group are referred to as

-   “heterocyclic ring-sulfanyl-carbonyl-oxy group.”

Among the groups represented by the formula (ω-6B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-oxy group,” and those groups where R^(a2) is aheterocyclic group are referred to as “heterocyclicring-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-7B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-8B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-thiocarbonyl-oxy group,” and those groups whereinR^(a2) is a heterocyclic group are referred to as

-   “heterocyclic ring-sulfanyl-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-9B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl-oxy group,” and those groups in which R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-carbamoyl-oxy group.”

Among the groups represented by the formula (ω-10B), those groups inwhich both R^(a2) and Rb2 are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-carbamoyl-oxy group,” those groups in which    both R^(a2) and R^(b2) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-carbamoyl-oxy group,” those groups in    which R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-carbamoyl-oxy group,” and those groups in which R^(a2) and Rb2    combine to each other, together with the nitrogen atom to which they    bind, to form a cyclicic amino group are referred to as-   “cyclicamino-carbonyl-oxy group.”

Among the groups represented by the formula (ω-11B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-oxy group,” and those groups in whichR^(a2) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-thiocarbamoyl-oxy group.”

Among the groups represented by the formula (ω-12B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-thiocarbamoyl-oxy group,” those groups in which    both R^(a2) and R^(b2) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-thiocarbamoyl-oxy group,” those groups in    which R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-thiocarbamoyl-oxy group,” and those groups in which R^(a2) and    Rb2 combine to each other, together with the nitrogen atom to which    they bind, to form a cyclic amino group are referred to as    “cyclicamino-thiocarbonyl-oxy group.”

Among the groups represented by the formula (ω-13B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-oxy group,” and those groups in which R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-sulfamoyl-oxy group.”

Among the groups represented by the formula (ω-14B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfamoyl-oxy group,” those groups in which    both R^(a2) and R^(b2) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfamoyl-oxy group,” those groups in    which R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-sulfamoyl-oxy group,” and those groups in which R^(a2) and    R^(b2) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-sulfonyl-oxy group.”

Among the groups represented by the formula (ω-15B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-oxy group,” and those groups where R^(a2) isa heterocyclic group are referred to as “N-heterocyclicring-sulfinamoyl-oxy group.”

Among the groups represented by the formula (ω-16B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfinamoyl-oxy group,” those groups in which    both R^(a2) and R^(b2) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfinamoyl-oxy group,” those groups in    which R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-sulfinamoyl-oxy group,” and those groups in which R^(a2) and    R^(b2) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-sulfinyl-oxy group.”

Among the groups represented by the formula (ω-17B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-oxy group,” and those groups in which R^(a2)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfonyl-oxy group.”

Among the groups represented by the formula (ω-18B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-oxy group,” those groups in which R^(a2) is aheterocyclic group are referred to as “heterocyclicring-oxy-sulfinyl-oxy group.”

Among the groups represented by the formula (ω-19B), those groups inwhich both R^(a2) and R^(b2) are hydrocarbon groups are referred to as

-   “O,O′-di(hydrocarbon)-phosphono-oxy group,” those groups in which    both R^(a2) and R^(b2) are heterocyclic groups are referred to as    “O,O′-di(heterocyclic ring)-phosphono-oxy group,” and those groups    in which R^(a2) is a hydrocarbon group and R^(b2) is a heterocyclic    group are referred to as “O-hydrocarbon substituted-O′-heterocyclic    ring substituted phophono-oxy group.”

Among the groups represented by the formula (ω-20B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-oxy group,” and those groups in which R^(a2) is aheterocyclic group referred to as “heterocyclic ring-sulfonyl-oxygroup.”

Among the groups represented by the formula (ω-21B), those groups inwhich R^(a2) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-oxy group,” and those groups in which R^(a2) is aheterocyclic group are referred to as “heterocyclic ring-sulfinyl-oxygroup.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1B) through (ω-21B) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-oxy group represented by the formula (ω-1B)include, for example, an alkyl-carbonyl-oxy group, analkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy group, acycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, acycloalkanedienyl-carbonyl-oxy group, and acycloalkyl-alkyl-carbonyl-oxy group, which are aliphatichydrocarbon-carbonyl-oxy groups; an aryl-carbonyl-oxy group; anaralkyl-carbonyl-oxy group; a bridged cyclic hydrocarbon-carbonyl-oxygroup; a spirocyclic hydrocarbon-carbonyl-oxy group; and a terpenefamily hydrocarbon-carbonyl-oxy group. In the following, groupsrepresented by the formulas (ω-2B) through (ω-21B) are similar to thoseexplained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1B) through (ω-21B) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl group represented by the formula (ω-1B) include, forexample, a monocyclic heteroaryl-carbonyl group, a fused polycyclicheteroaryl-carbonyl group, a monocyclic non-aromatic heterocyclicring-carbonyl group, and a fused polycyclic non-aromatic heterocyclicring-carbonyl group. In the following, groups represented by theformulas (ω-2B) through (ω-21B) are similar to those groups explainedabove.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10B) through (ω-16B) include similar groupsto the aforementioned cyclic amino group.

The aforementioned acyl-oxy group, hydrocarbon-oxy group, andheterocyclic-oxy group are generically referred to as “substituted oxygroup.” Moreover, these substituted oxy group and hydroxy group aregenerically referred to as “hydroxy group which may be substituted.”

Examples of the acyl-sulfanyl group include the groups in which hydrogenatom of sulfanyl group is substituted with acyl group, and include, forexample, formylsulfanyl group, glyoxyloylsulfanyl group,thioformylsulfanyl group, carbamoyloxy group, thicarbamoyloxy group,sulfamoyloxy group, sulfinamoyloxy group, carboxyoxy group, sulphooxygroup, phosphonooxy group, and groups represented by the followingformulas:

-   wherein R^(a3) and R^(b3) may be the same or different and represent    a hydrocarbon group which may be substituted or a heterocyclic group    which may be substituted, or R^(a3) and R^(b3) combine to each    other, together with the nitrogen atom to which they bind, to form a    cyclic amino group which may be substituted.

In the definition of the aforementioned acyl-sulfanyl group, among thegroups represented by the formula (ω-1C), those groups in which R^(a3)is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-sulfanylgroup,” and those groups in which R^(a3) is a heterocyclic group arereferred to as “heterocyclic ring-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-2C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-3C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-carbonyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-4C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as

-   “hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group,” and those groups    in which R^(a3) is a heterocyclic group are referred to as    “heterocyclic ring-oxy-carbonyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-5C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-sulfanyl group,” and those groups inwhich R^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-sulfanyl-carbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-6C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-7C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-8C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as

-   “hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group,” and those groups    in which R^(a3) is a heterocyclic group are referred to as    “heterocyclic ring-sulfanyl-thiocarbonyl-sulfanyl group.”

Among the groups represented by the formula (ω-9C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-carbamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-10C), those groups inwhich both R^(a3) and R^(b3) are a hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-carbamoyl-sulfanyl group,” those groups in    which both R^(a3) and R^(b3) are heterocyclic groups are referred to    as “N,N-di(heterocyclic ring)-carbamoyl-sulfanyl group,” those    groups in which R^(a3) is a hydrocarbon group and R^(b3) is a    heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic    ring-carbamoyl-sulfanyl group,” and those groups in which R^(a3) and    R^(b3) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclicamino-carbonyl-sulfamoyl group.”

Among the groups represented by the formula (ω-11C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-thiocarbamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-12C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group,” those groups in    which and R^(a3) and R^(b3) are heterocyclic groups are referred to    as “N,N-di(heterocyclic ring)-thiocarbamoyl-sulfanyl group,” those    groups in which R^(a3) is a hydrocarbon group and R^(b3) is a    heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic    ring-thiocarbamoyl-sulfanyl group,” and those groups in which R^(a3)    and R^(b3) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclicamino-thiocarbonyl-sulfamoyl group.”

Among the groups represented by the formula (ω-13C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-sulfamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-14C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfamoyl-sulfanyl group,” those groups in    which both R^(a3) and R^(b3) are heterocyclic groups are referred to    as “N,N-di(heterocyclic ring)-sulfamoyl-sulfinyl group,” those    groups in which R^(a3) is a hydrocarbon group and R^(b3) is a    heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic    ring-sulfamoyl-sulfanyl group,” and those groups in which R^(a3) and    R^(b3) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclicamino-sulfonyl-sulfanyl group.”

Among the groups represented by the formula (ω-15C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-sulfinamoyl-sulfanyl group.”

Among the groups represented by the formula (ω-16C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl group,” those groups in    which both R^(a3) and R^(b3) are heterocyclic groups are referred to    as “N,N-di(heterocyclic ring)-sulfinamoyl-sulfanyl group,” those    groups in which R^(a3) is a hydrocarbon group and R^(b3) is a    heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic    ring-sulfinamoyl-sulfanyl group,” and those groups in which R^(a3)    and R^(b3) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclicamino-sulfanyl-sulfanyl group.”

Among the groups represented by the formula (ω-17C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-sulfonyl-sulfanyl group.”

Among the groups represented by the formula (ω-18C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-sulfanyl group,” and those groups in whichR^(a3) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-sulfinyl-sulfanyl group.”

Among the groups represented by the formula (ω-19C), those groups inwhich both R^(a3) and R^(b3) are hydrocarbon groups are referred to as

-   “O,O′-di(hydrocarbon)-phosphono-sulfanyl group,” those groups in    which both R^(a3) and R^(b3) are heterocyclic groups are referred to    as “O,O′-di(heterocyclic ring)-phosphono-sulfanyl group,” and those    groups in which R^(a3) is a hydrocarbon group and R^(b3) is a    heterocyclic group are referred to as “O-hydrocarbon-O′-heterocyclic    ring-phosphono-sulfanyl group.”

Among the groups represented by the formula (ω-20C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-sulfanyl group,” and those groups in which R^(a3)is a heterocyclic group are referred to as “heterocyclicring-sulfonyl-sulfanyl group.”

Among the groups represented by the formula (ω-21C), those groups inwhich R^(a3) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-sulfanyl group,” and those groups in which R^(a3)is a heterocyclic group are referred to as “heterocyclicring-sulfinyl-sulfanyl group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1C) through (ω-21C) include similar groups tothe aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-sulfanyl group represented by the formula (ω-1C)include, for example, an alkyl-carbonyl-sulfanyl group, analkenyl-carbonyl-sulfanyl group, an alkynyl-carbonyl-sulfanyl group, acycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbonyl-sulfanylgroup, a cycloalkanedienyl-carbonyl-sulfanyl group, acycloalkyl-alkyl-carbonyl-sulfanyl group which are aliphatichydrocarbon-carbonyl-sulfanyl groups; an aryl-carbonyl-sulfanyl group;an aralkyl-carbonyl-sulfanyl group; a bridged cyclichydrocarbon-carbonyl-sulfanyl group; a spiro cyclichydrocarbon-carbonyl-sulfanyl group; and a terpene familyhydrocarbon-carbonyl-sulfanyl group. In the following, groupsrepresented by the formulas (ω-2C) through (ω-21C) are similar to thoseexplained above.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1C) through (ω-21C) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl-sulfanyl group represented by the formula (ω-1C) include,for example, a monocyclic heteroaryl-carbonyl-sulfanyl group, a fusedpolycyclic heteroaryl-carbonyl-sulfanyl group, a monocyclic non-aromaticheterocyclic ring-carbonyl-sulfanyl group, and a fused polycyclicnon-aromatic heterocyclic ring-carbonyl-sulfanyl group. In thefollowing, groups represented by the formula (ω-2C) through (ω-21C) aresimilar to those groups explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-1C) through (ω-16C) include similar groups tothe aforementioned cyclic amino group.

The aforementioned acyl-sulfanyl group, hydrocarbon-sulfanyl group, andheterocyclic-sulfanyl group are generically referred to as “substitutedsulfanyl group.” Moreover, these substituted sulfanyl group and sulfanylgroup are generically referred to as “sulfanyl group which may besubstituted.”

Examples of the N-hydrocarbon-amino group include the groups in whichone hydrogen atom of amino group is substituted with a hydrocarbongroup, and include, for example, an N-alkyl-amino group, anN-alkenyl-amino group, an N-alkynyl-amino group, an N-cycloalkyl-aminogroup, an N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, and anN-aralkyl-amino group.

Examples of the N-alkyl-amino group include, for example, methylamino,ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino,sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino,(2-methylbutyl)amino, (1-methylbutyl)amino, neopentylamino,(1,2-dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexylamino,(4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino,(1-methylpentyl)amino, (3,3-dimethylbutyl)amino,(2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino,(1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino,(2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, (1-ethylbutyl)amino,(1-ethyl-1-methylpropyl)amino, n-heptylamino, n-octylamino,n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino,n-tridecylamino, n-tetradecylamino, and n-pentadecylamino, which are C₁to C₁₅ straight chain or branched chain N-alkyl amino groups.

Examples of the N-alkenyl-amino group include, for example, vinyl amino,(prop-1-en-1-yl)amino, allylamino, isopropenylamino,(but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino,(2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino,(pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino, (pent-3-en-1-yl)amino,(pent-4-en-1-yl)amino, (3-methylbut-2-en-1-yl)amino,(3-methylbut-3-en-1-yl)amino, (hex-1-en-1-yl)amino,(hex-2-en-1-yl)amino, (hex-3-en-1-yl)amino, (hex-4-en-1-yl)amino,(hex-5-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino,(4-methylpent-3-en-1-yl)amino, (hept-1-en-1-yl)amino,(hept-6-en-1-yl)amino, (oct-1-en-1-yl)amino, (oct-7-en-1-yl)amino,(non-1-en-1-yl)amino, (non-8-en-1-yl)amino, (dec-1-en-1-yl)amino,(dec-9-en-1-yl)amino, (undec-1-en-1-yl)amino, (undec-10-en-1-yl)amino,(dodec-1-en-1-yl)amino, (dodec-11-en-1-yl)amino,(tridec-1-en-1-yl)amino, (tridec-12-en-1-yl)amino,(tetradec-1-en-1-yl)amino, (tetradec-13-en-1-yl)amino,(pentadec-1-en-1-yl)amino, and (pentadec-14-en-1-yl)amino, which are C₂to C₁₅ straight chain or branched chain N-alkenyl amino groups.

Examples of the N-alkynyl-amino group include, for example,ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino,(but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino,(1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino,(pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino,(hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino,(oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (non-8-yn-1-yl)amino,(dec-1-yn-1-yl)amino, (dec-9-yn-1-yl)amino, (undec-1-yn-1-yl)amino,(undec-10-yn-1-yl)amino, (dodec-1-yn-1-yl)amino,(dodec-11-yn-1-yl)amino, (tridec-1-yn-1-yl)amino,(tridec-12-yn-1-yl)amino, (tetradec-1-yn-1-yl)amino,(tetradec-13-yn-1-yl)amino, (pentadec-1-yn-1-yl)amino, and(pentadec-14-yn-1-yl)amino, which are C₂ to C₁₅ straight chain orbranched chain N-alkynyl-amino groups.

Examples of the N-cycloalkyl-amino group include, for example,cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino,cycloheptylamino, and cyclooctylamino, which are C₃ to C₈N-cycloalkyl-amino groups.

Examples of the N-cycloalkyl-alkyl-amino group include, for example,(cyclopropylmethyl)amino, (1-cyclopropylethyl)amino,(2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino,(4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino,(6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino,(cyclopentylmethyl)amino, (cyclobutylmethyl)amino,(cyclopentylmethyl)amino, (cyclohexylmethyl)amino,(2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino,(4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino,(cyclooctylmethyl)amino, and (6-cyclooctylhexyl)amino, which are C₄ toC₁₄ N-cycloalkyl-alkyl-amino groups.

Examples of the N-aryl-amino group include, for example, phenylamino,1-naphthylamino, 2-naphtylamino, anthrylamino, phenanthrylamino, andacenaphthylenylamino, which are C₆ to C₁₄ N-mono-arylamino groups.

Examples of the N-aralkyl-amino group include, for example, benzylamino,(1-naphthylmethyl)amino, (2-naphthylmethyl)amino,(anthracenylmethyl)amino, (phenanthrenylmethyl)amino,(acenaphthylenylmethyl)amino, (diphenylmethyl)amino, (1-phenethyl)amino,(2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino,(1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino,(2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino,(3-(1-naphthyl)propyl)amino, (3-(2-naphthyl)propyl)amino,(4-phenylbutyl)amino, (4-(1-naphthyl)butyl)amino,(4-(2-naphthyl)butyl)amino, (5-phenylpentyl)amino,(5-(1-naphthyl)pentyl)amino, (5-(2-naphthyl)pentyl)amino,(6-phenylhexyl)amino, (6-(1-naphthyl)hexyl)amino, and(6-(2-naphthyl)hexyl)amino, which are C₇ to C16 N-aralkyl-amino groups.

Examples of the N,N-di(hydrocarbon)-amino group include the groups inwhich two hydrogen atoms of amino group are substituted with hydrocarbongroups, and include, for example, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N,N-di-n-propylamino, N,N-diisopropylamino,N-allyl-N-methylamino, N-(prop-2-yn-1-yl)-N-methylamino,N,N-dicyclohexylamino, N-cyclohexyl-N-methylamino,N-cyclohexylmethylamino-N-methylamino, N,N-diphenylamino,N-methyl-N-phenylamino, N,N-dibenzylamino, and N-benzyl-N-methylamino.

Examples of the N-heterocyclic ring-amino group include the groups inwhich one hydrogen atom of amino group is substituted with aheterocyclic group, and include, for example, (3-pyrrolizinyl)amino,(4-piperidinyl)amino, (2-tetrahydropyranyl)amino, (3-indolinyl)amino,(4-chromanyl)amino, (3-thienyl)amino, (3-pyridyl)amino,(3-quinolyl)amino, and (5-indolyl)amino.

Examples of the N-hydrocarbon-N-heterocyclic ring-amino group includethe groups in which two hydrogen atoms of amino group are substitutedwith hydrocarbon group and heterocyclic group respectively, and include,for example, N-methyl-N-(4-piperidinyl)amino,N-(4-chromanyl)-N-methylamino, N-methyl-N-(3-thienyl)amino,N-methyl-N-(3-pyridyl)amino, N-methyl-N-(3-quinolyl)amino.

Examples of the acyl-amino group include the groups in which onehydrogen atom of the amino group is substituted with an acyl group, andinclude, for example, formylamino group, glyoxyloylamino group,thioformylamino group, carbamoylamino group, thiocarbamoylamino group,sulfamoylamino group, sulfinamoylamino group, carboxyamino group,sulphoamino group, phosphonoamino group, and groups represented by thefollowing formulas:

-   wherein R^(a4) and R^(b4) may be the same or different and represent    a hydrocarbon group which may be substituted or a heterocyclic group    which may be substituted, or R^(a4) and R^(b4) combine to each    other, together with the nitrogen atom to which they bind, to form a    cyclic amino group which may be substituted.

In the definition of the aforementioned acyl-amino group, among thegroups represented by the formula (ω-1D), those groups in which R^(a4)is a hydrocarbon group are referred to as “hydrocarbon-carbonyl-aminogroup,” and those groups in which R^(a4) is a heterocyclic group arereferred to as “heterocyclic ring-carbonyl-amino group.”

Among the groups represented by the formula (ω-2D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-carbonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-carbonyl-amino group.”

Among the groups represented by the formula (ω-3D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-carbonyl-carbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as

-   “heterocyclic ring-carbonyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-4D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as

-   “hydrocarbon-oxy-carbonyl-carbonyl-amino group,” and those groups in    which R^(a4) is a heterocyclic group are referred to as    “heterocyclic ring-oxy-carbonyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-5D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfanyl-carbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as

-   “heterocyclic ring-sulfanyl-carbonyl-amino group.”

Among the groups represented by the formula (ω-6D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-thiocarbonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-7D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-thiocarbonyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as

-   “heterocyclic ring-oxy-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-8D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as

-   “hydrocarbon-sulfanyl-thiocarbonyl-amino group,” and those groups in    which R^(a4) is a heterocyclic group are referred to as    “heterocyclic ring-sulfanyl-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-9D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-carbamoyl group,” and those groups in which R^(a4) is aheterocyclic group are referred to as “N-heterocyclicring-carbamoyl-amino group.”

Among the groups represented by the formula (ω-10D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-carbamoyl-amino group,” those groups in which    both R^(a4) and R^(b4) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-carbamoyl-amino group,” those groups in    which R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-carbamoyl-amino group,” and those groups in which R^(a4) and    R^(b4) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-carbonyl-amino group.”

Among the groups represented by the formula (ω-11D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-thiocarbamoyl-amino group,” and those groups in whichR^(a4) is a heterocyclic ring group are referred to as

-   “N-heterocyclic-thiocarbamoyl-amino group.”

Among the groups represented by the formula (ω-12D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-thiocarbamoyl-amino group,” those groups in    which both R^(a4) and R^(b4) are heterocyclic groups are referred to    as “N,N-di(heterocyclic ring)-thiocarbamoyl-amino group,” those    groups in which R^(a4) is a hydrocarbon group and R^(b4) is a    heterocyclic group are referred to as “N-hydrocarbon-N-heterocyclic    ring-thiocarbamoyl-amino group,” and those groups in which R^(a4)    and R^(b4) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-thiocarbonyl-amino group.”

Among the groups represented by the formula (ω-13D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfamoyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “N-heterocyclicring-sulfamoyl-amino group.”

Among the groups represented by the formula (ω-14D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as

-   “di(hydrocarbon)-sulfamoyl-amino group,” those groups in which both    R^(a4) and R^(b4) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfamoyl-amino group,” those groups in    which R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic    group are referred to as “N-hydrocarbon-N-heterocyclic    ring-sulfamoyl-amino group,” and those groups in which R^(a4) and    R^(b4) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino group are referred to as    “cyclic amino-sulfonyl-amino group.”

Among the groups represented by the formula (ω-15D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“N-hydrocarbon-sulfinamoyl-amino group,” and those groups in whichR^(a4) is a heterocyclic group are referred to as

-   “N-heterocyclic ring-sulfinamoyl-amino group.”

Among the groups represented by the formula (ω-16D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as

-   “N,N-di(hydrocarbon)-sulfinamoyl-amino group,” those groups in which    both R^(a4) and R^(b4) are heterocyclic groups are referred to as    “N,N-di(heterocyclic ring)-sulfinamoyl-amino group,” groups in which    R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic group are    referred to as “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-amino    group,” and those groups in which R^(a4) and R^(b4) combine to each    other, together with the nitrogen atom to which they bind, to form a    cyclic amino group are referred to as “cyclic amino-sulfinyl-amino    group.”

Among the groups represented by the formula (ω-17D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfonyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfoyl-amino group.”

Among the groups represented by the formula (ω-18D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-oxy-sulfinyl-amino group,” and those groups in which R^(a4)is a heterocyclic group are referred to as “heterocyclicring-oxy-sulfinyl-amino group.”

Among the groups represented by the formula (ω-19D), those groups inwhich both R^(a4) and R^(b4) are hydrocarbon groups are referred to as

-   “O,O′-di(hydrocarbon)-phosphono-amino group,” those groups in which    both R^(a4) and R^(b4) are heterocyclic groups are referred to as    “O,O′-di(heterocyclic ring)-phosphono-amino group,” and those groups    in which R^(a4) is a hydrocarbon group and R^(b4) is a heterocyclic    group are referred to as “O-hydrocarbon-O′-heterocyclic    ring-phosphono-amino group.”

Among the groups represented by the formula (ω-20D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfonyl-amino group,” and those groups in which R^(a4) isa heterocyclic group are referred to as “heterocyclicring-sulfonyl-amino group.”

Among the groups represented by the formula (ω-21D), those groups inwhich R^(a4) is a hydrocarbon group are referred to as“hydrocarbon-sulfinyl-amino group,” and those groups in which R^(a4) isa heterocyclic group are referred to as “heterocyclicring-sulfinyl-amino group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1D) through (ω-21D) include the similargroups to the aforementioned hydrocarbon group. Examples of thehydrocarbon-carbonyl-amino groups represented by the formula (ω-1D)include, for example, an alkyl-carbonyl-amino group, analkenyl-carbonyl-amino group, an alkynyl-carbonyl-amino group, acycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl-amino group, acycloalkanedienyl-carbonyl-amino group, acycloalkyl-alkyl-carbonyl-amino group which are aliphatichydrocarbon-carbonyl-amino groups; an aryl-carbonyl-amino group; anaralkyl-carbonyl-amino group; a bridged cyclichydrocarbon-carbonyl-amino group; a spiro cyclichydrocarbon-carbonyl-amino group; and a terpene familyhydrocarbon-carbonyl-amino group. In the following, groups representedby the formulas (ω-2D) through (ω-21D) are similar to those explainedabove.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1D) through (ω-21D) include similar groups tothe aforementioned heterocyclic group. Examples of the heterocyclicring-carbonyl-amino group represented by the formula (ω-1D) include, forexample, a monocyclic heteroaryl-carbonyl-amino group, a fusedpolycyclic heteroaryl-carbonyl-amino group, a monocyclic non-aromaticheterocyclic-carbonyl-amino group, and a fused polycyclic non-aromaticheterocyclic-carbonyl-amino group. In the following, groups representedby the formulas (ω-2D) through (ω-21D) are similar to those groupsexplained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10D) through (ω-16D) include similar groupsto the aforementioned cyclic amino group.

Examples of the di(acyl)-amino group include the groups in which twohydrogen atoms of amino group are substituted with acyl groups in thedefinitions of the aforementioned substituents according to “which maybe substituted.” Examples include, for example, di(formyl)-amino group,di(glyoxyloyl)-amino group, di(thioformyl)-amino group,di(carbamoyl)-amino group, di(thiocarbamoyl)-amino group,di(sulfamoyl)-amino group, di(sulfinamoyl)-amino group,di(carboxy)-amino group, di(sulfo)-amino group, di(phosphono)-aminogroup, and groups represented by the following formulas:

-   wherein R^(a5) and R^(b5) may be the same or different and represent    hydrogen atom, a hydrocarbon group which may be substituted or a    heterocyclic group which may be substituted, or R^(a5) and R^(b5)    combine to each other, together with the nitrogen atom to which they    bind, to form a cyclic amino group which may be substituted.

In the definition of aforementioned di(acyl)-amino group, among thegroups represented by the formula (ω-1E), those groups in which R^(a5)is a hydrocarbon group are referred to as“bis(hydrocarbon-carbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-carbonyl)-amino group.

Among the groups represented by the formula (ω-2E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-carbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as “bis(heterocyclicring-oxy-carbonyl)-amino group.”

Among the groups represented by the formula (ω-3E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(hydrocarbon-carbonyl-carbonyl)-amino group,” and those groups    in which R^(a5) is a heterocyclic group are referred to as    “bis(heterocyclic ring-carbonyl-carbonyl)-amino group.

Among the groups represented by the formula (ω-4E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino group,” and those    groups in which R^(a5) is a heterocyclic group are referred to as    “bis(heterocyclic ring-oxy-carbonyl-carbonyl)-amino group.”

Among the groups represented by the formula (ω-5E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(hydrocarbon-sulfanyl-carbonyl)-amino group,” and those groups    in which R^(a5) is a heterocyclic group are referred to as    “bis(heterocyclic ring-sulfanyl-carbonyl)-amino group.”

Among the groups represented by the formula (ω-6E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-thiocarbonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(heterocyclic ring-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-7E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(hydrocarbon-oxy-thiocarbonyl)-amino group,” and those groups in    which R^(a5) is a heterocyclic group are referred to as    “bis(heterocyclic ring-oxy-thiocarbonyl)-amino group.

Among the groups represented by the formula (ω-8E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino group,” and those    groups in which R^(a5) is a heterocyclic group are referred to as    “bis(heterocyclic ring-sulfanyl-thiocarbonyl)-amino group.”

Among the groups represented by the formula (ω-9E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-carbamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(N-heterocyclic ring-carbamoyl)-amino group.”

Among the groups represented by the formula (ω-10E), those groups inwhich both R^(a5) and Rb5 are hydrocarbon groups are referred to as

-   “bis[N,N-di(hydrocarbon)-carbamoyl]-amino group,” those groups in    which both R^(a5) and R^(b5) are heterocyclic groups are referred to    as “bis[N,N-di(heterocyclic ring)-carbamoyl]-amino group,” groups in    which R^(a5) is a hydrocarbon group and R^(b5) is a heterocyclic    group are referred to as “bis(N-hydrocarbon-N-heterocyclic    ring-carbamoyl)-amino group,” and those groups in which R^(a5) and    R^(b5) combine to each other, together with the nitrogen atom to    which they bind, to form a cyclic amino groups are referred to as    “bis(cyclic amino-carbonyl)amino group.”

Among the groups represented by the formula (ω-11E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as

-   “bis(N-hydrocarbon-thiocarbamoyl)-amino group,” and those groups in    which R^(a5) is a heterocyclic group are referred to as    “bis(N-heterocyclic ring-thiocarbamoyl)-amino group.”

Among the groups represented by the formula (ω-12E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as

-   “bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group,” those groups    in which both R^(a5) and R^(b5) are heterocyclic groups are referred    to as “bis[N,N-di(heterocyclic ring)-thiocarbamoyl]-amino group,”    those groups in which R^(a5) is a hydrocarbon group and R^(b5) is a    heterocyclic group are referred to as    “bis(N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl)-amino group,”    and those groups in which R^(a5) and R^(b5) combine to each other,    together with the nitrogen atom to which they bind, to form a cyclic    amino group are referred to as “bis(cyclic amino-thiocarbonyl)-amino    group.”

Among the groups represented by the formula (ω-13E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-sulfamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(N-heterocyclic ring-sulfamoyl)-amino group.”

Among the groups represented by the formula (ω-14E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as

-   “bis[N,N-di(hydrocarbon)-sulfamoyl]-amino group,” those groups in    which both R^(a5) and R^(b5) are heterocyclic groups are referred to    as “bis[N,N-di(heterocyclic ring)-sulfamoyl]-amino group,” those    groups in which R^(a5) is a hydrocarbon group and R^(b5) is a    heterocyclic group are referred to as    “bis(N-hydrocarbon-N-heterocyclic ring-sulfamoyl)-amino group,” and    those groups in which R^(a5) and R^(b5) combine to each other,    together with the nitrogen atom to which they bind, to form a cyclic    amino group are referred to as “bis(cyclic amino-sulfonyl)amino    group.”

Among the groups represented by the formula (ω-15E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(N-hydrocarbon-sulfinamoyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(N-heterocyclic ring-sulfinamoyl)-amino group.”

Among the groups represented by the formula (ω-16E), those groups inwhich R^(a5) and R^(b5) are hydrocarbon groups are referred to as

-   “bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino group,” those groups in    which R^(a5) and R^(b5) are heterocyclic groups are referred to as    “bis[N,N-di(heterocyclic ring)-sulfinamoyl]-amino group,” those    groups in which R^(a5) is a hydrocarbon group and R^(b5) is a    heterocyclic group are referred to as    “bis(N-hydrocarbon-N-heterocyclic ring-sulfinamoyl)-amino group,”    and those groups in which R^(a5) and R^(b5) combine to each other,    together with the nitrogen atom to which they bind, to form a cyclic    amino group are referred to as “bis(cyclic amino-sulfinyl)amino    group.”

Among the groups represented by the formula (ω-17E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-sulfonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(heterocyclic ring-oxy-sulfonyl)-amino group.”

Among the groups represented by the formula (ω-18E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-oxy-sulfinyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(heterocyclic ring-oxy-sulfinyl)-amino group.”

Among the groups represented by the formula (ω-19E), those groups inwhich both R^(a5) and R^(b5) are hydrocarbon groups are referred to as

-   “bis[O,O′-di(hydrocarbon)-phosphono]-amino group,” those groups in    which both R^(a5) and R^(b5) are heterocyclic groups are referred to    as “bis[O,O′-di(heterocyclic ring)-phosphono]-amino group,” and    those groups in which R^(a5) is a hydrocarbon group and R^(b5) is a    heterocyclic group are referred to as    “bis(O-hydrocarbon-O′-heterocyclic ring-phosphono)-amino group.”

Among the groups represented by the formula (ω-20E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfonyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(heterocyclic ring-sulfonyl)-amino group.”

Among the groups represented by the formula (ω-21E), those groups inwhich R^(a5) is a hydrocarbon group are referred to as“bis(hydrocarbon-sulfinyl)-amino group,” and those groups in whichR^(a5) is a heterocyclic group are referred to as

-   “bis(heterocyclic ring-sulfinyl)-amino group.”

Examples of the hydrocarbon in the groups represented by theaforementioned formulas (ω-1E) through (ω-21E) include the similargroups to the aforementioned hydrocarbon group. Examples of thebis(hydrocarbon-carbonyl)-amino groups represented by the formula (ω-1E)include, for example, a bis(alkyl-carbonyl)-amino group, abis(alkenyl-carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino group,a bis(cycloalkyl-carbonyl)-amino group, abis(cycloalkenyl-carbonyl)-amino group, abis(cycloalkanedienyl-carbonyl)-amino group, abis(cycloalkyl-alkyl-carbonyl)-amino group which are bis(aliphatichydrocarbon-carbonyl)-amino groups; a bis(aryl-carbonyl)-amino group; abis(aralkyl-carbonyl)-amino group; a bis(bridged cyclichydrocarbon-carbonyl)-amino group; a bis(spiro cyclichydrocarbon-carbonyl)-amino group; and a bis(terpene familyhydrocarbon-carbonyl)-amino group. In the following, groups representedby the formulas (ω-2E) through (ω-21E) are similar to those explainedabove.

Examples of the heterocyclic ring in the groups represented by theaforementioned formulas (ω-1E) through (ω-21E) include similar groups tothe aforementioned heterocyclic group. Examples of the bis(heterocyclicring-carbonyl)-amino group represented by the formula (ω-1E) include,for example, a bis(monocyclic heteroaryl-carbonyl)-amino group, abis(fused polycyclic heteroaryl-carbonyl)-amino group, a bis(monocyclicnon-aromatic heterocyclic-carbonyl)-amino group, and a bis(fusedpolycyclic non-aromatic heterocyclic-carbonyl)-amino group. In thefollowing, groups represented by the formulas (ω-2E) through (ω-21E) aresimilar to those groups explained above.

Examples of the cyclic amino in the groups represented by theaforementioned formulas (ω-10E) through (ω-16E) include similar groupsto the aforementioned cyclic amino group.

The aforementioned acyl-amino group and di(acyl)-amino group aregenerically referred to as “acyl substituted amino group.” Furthermore,the aforementioned N-hydrocarbon-amino group, N,N-di(hydrocarbon)-aminogroup, N-heterocyclic-amino group, N-hydrocarbon-N-heterocyclic-aminogroup, cyclic amino group, acyl-amino group, and di(acyl)-amino groupare generically referred to as

-   “substituted amino group.”

In the following, compounds represented by the aforementioned generalformula (I) are explained in details.

“Connecting group whose number of atoms of main chain is 2 to 5” in thedefinition of X means connecting groups wherein 2 to 5 atoms in a mainchain link together between rings Z and E. The aforementioned “number ofatoms of the main chain” is counted so as to minimize the number ofconnecting atoms existing between the rings Z and E, regardless of thepresence or absence of hetero atom(s). For example, the number of atomsof 1,2-cyclopentylene is counted as 2, the number of atoms of1,3-cyclopentylene is counted as 3, the number of atoms of 1,4-phenyleneis counted as 4, and the number of atoms of 2,6-pyridine-diyl is countedas 3.

The aforementioned “connecting group whose number of atoms of main chainis 2 to 5” is formed by one functional group selected from the followinggroup of divalent group ζ-1, or formed by combining 2 to 4 functionalgroups of 1 to 4 kinds selected from the following divalent group ζ-2.

-   [Divalent Group ζ-1] the Following Formulas:-   [Divalent Group ζ-2] the Following Formulas:-   When 2 or more divalent groups combine, each group may be the same    or different.

The aforementioned “connecting group wherein the number of atoms of themain chain is 2 to 5,” is preferably a group selected from the following“connecting group α.”

-   [Connecting Group α] the Following Formulas:-   wherein a bond at the left end binds to ring Z and a bond at the    right end binds to E.

The group represented by the following formula is most preferred:

-   wherein the bond at the left end binds to ring Z and the bond at the    right end binds to E.

Examples of the substituent, according to “connecting group which may besubstituted” in the definition of “a connecting group whose number ofatoms of the main chain is 2 to 5,” include similar groups to thesubstituents in the definition of the aforementioned “which may besubstituted.” A C₁ to C₆ alkyl group is preferred, and a methyl group ismore preferred. The substituent may combine with a substituent of thering E or Z, together with atoms to which they bind, to form a cyclicgroup which may be substituted. Examples include the compoundsrepresented by the general formula (I) being those represented by thefollowing formulas:

In the aforementioned general formula (I), examples of A includehydrogen atom or acetyl group, and hydrogen atom is preferred.

Examples of the “arene” in “an arene which may have one or moresubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined above” in the definition of ring Z include a monocyclicor fused heterocyclic aromatic hydrocarbon, and include, for example,benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, andacenaphylene ring. C₆ to C₁₀ arenes such as benzene ring, naphthalenering and the like are preferred, benzene ring and naphthalene ring aremore preferred, and benzene ring is most preferred.

Examples of the substituent in the definition of “an arene which mayhave one or more substituents in addition to the group represented byformula —O-A wherein A has the same meaning as that defined above andthe group represented by formula —X-E wherein each of X and E has thesame meaning as that defined above” in the aforementioned definition ofring Z include similar groups to the substituent explained for thedefinition “which may be substituted.” The position of substituentsexisting on the arene is not particularly limited, and when two or moresubstituents exist, they may be the same or different.

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —X-E whereineach of X and E has the same meaning as that defined above” in theaforementioned definition of ring Z is “a benzene ring which may haveone or more substituents in addition to the group represented by formula—O-A wherein A has the same meaning as that defined above and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined above,” “a benzene ring which has one to threesubstituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined above” is preferred, and “a benzene ring which has onesubstituent in addition to the group represented by formula —O-A whereinA has the same meaning as that defined above and the group representedby formula —X-E wherein each of X and E has the same meaning as thatdefined above” is more preferred. Preferred examples of saidsubstituents include groups selected from the following SubstituentGroup γ-1z. Halogen atom and tert-butyl group [(1,1-dimethyl)ethylgroup] are more preferred, and halogen atom is most preferred.

-   [Substituent Group γ-1z] halogen atom, nitro group, cyano group,    hydroxy group, methoxy group, methyl group, isopropyl group,    tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl    group, 2,2-dicyanoethen-1-yl group,    2-cyano-2-(methoxycarbonyl)ethen-1-yl group,    2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl    group, (trimethylsilyl)ethynyl group, trifluoromethyl group,    pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl    group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl    group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group,    1-[(benzyloxy)imino]ethyl group, 2-thienyl group [thiophen-2-yl    group], 3-thienyl group [thiophen-3-yl group], 1-pyrrolyl group    [pyrrol-1-yl group], 2-methylthiazol-4-yl group,    imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group [pyridin-2-yl    group], acetyl group, isobutyryl group, piperidinocarbonyl group,    4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group,    carboxy group, methoxycarbonyl group,    N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,    N,N-dimethylcarbamoyl group, sulfamoyl group,    N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,    N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,    acetylamino group, benzoylamino group, methanesulfonylamino group,    benzenesulfonylamino group, 3-phenylureido group,    (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and    {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —X-E whereineach of X and E has the same meaning as that defined above” in theaforementioned definition of ring Z is “a benzene ring which may haveone or more substituents in addition to the group represented by formula—O-A wherein A has the same meaning as that defined above and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined above,” it is most preferable that one substituentexists and locates on the position of R^(z) when the following partialformula (Iz-1) in the general formula containing ring Z

-   is represented by the following formula (Iz-2).-   At this time, said substituents can be defined as R^(z). Preferred    examples of R^(z) include a group selected from the following    Substituent Group γ-2z. Halogen atom and tert-butyl group are more    preferred, and halogen atom is most preferred.-   [Substituent Group γ-2z] halogen atom, nitro group, cyano group,    methoxy group, methyl group, isopropyl group, tert-butyl group,    1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group,    2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl    group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group,    phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl    group, pentafluoroethyl group, phenyl group,    4-(trifluoromethyl)phenyl group, 4-fluorophenyl group,    2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group,    1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group,    2-thienyl group, 3-thienyl group, 1-pyrrolyl group,    2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group,    2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl    group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl    group, carboxy group, methoxycarbonyl group,    N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,    N,N-dimethylcarbamoyl group, sulfamoyl group,    N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,    N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,    acetylamino group, benzoylamino group, methanesulfonylamino group,    benzenesulfonylamino group, 3-phenylureido group,    (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and    {[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group

When “an arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined above and the group represented by formula —X-E whereineach of X and E has the same meaning as that defined above” in theaforementioned definition of ring Z is “a naphthalene ring which mayhave one or more substituents in addition to the group represented byformula —O-A wherein A has the same meaning as that defined above andthe group represented by formula —X-E wherein each of X and E has thesame meaning as that defined above,” naphthalene ring is preferred.

Examples of the “hetero arene” in “a hetero arene which may have one ormore substituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined above and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined above” in the aforementioned definition of ring Zinclude a monocyclic or a fused polycyclic aromatic heterocyclic ringscontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom and the like asring-constituting atoms (ring forming atoms), and include, for example,furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring,thiazole ring, isothiazole ring, imidazole ring, pyrazole ring,1,2,3-oxadiazole ring, 1,2,3-thiadiazole ring, 1,2,3-triazole ring,pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring,1,2,3-triazine ring, 1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepinering, 1,4-thiazepine ring, benzofuran ring, isobenzofuran ring,benzo[b]thiophene ring, benzo[c]thiophene ring, indole ring,2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzoxazole ring,1,2-benzisoxazole ring, 2,1-benzisoxazole ring, benzothiazole ring,1,2-benzisothiazole ring, 2,1-benzisothiazole ring, 1,2,3-benzoxadiazolring, 2,1,3-benzoxadiazol ring, 1,2,3-benzothiadiazole ring,2,1,3-benzothiadiazole ring, 1H-benzotriazole ring, 2H-benzotriazolering, quinoline ring, isoquinoline ring, cinnoline ring, quinazolinering, quinoxaline ring, phthalazine ring, naphthyridine ring,1H-1,5-benzodiazepine ring, carbazole ring, α-carboline ring,β-carboline ring, γ-carboline ring, acridine ring, phenoxazine ring,phenothiazine ring, phenazine ring, phenanthridine ring, phenanthrolinering, thianthrene ring, indolizine ring, and phenoxathiine ring, whichare 5 to 14-membered monocyclic or fused polycyclic aromaticheterocyclic rings. 5 to 13-membered monocyclic or fused polycyclicaromatic heterocyclic rings are preferred, and thiophene ring, pyridinering, indole ring, quinoxaline ring, and carbazole ring are morepreferred.

Examples of the substituent in the definition of “a hetero arene whichmay have one or more substituents in addition to the group representedby formula —O-A wherein A has the same meaning as that defined above andthe group represented by formula —X-E wherein each of X and E has thesame meaning as that defined above” in the aforementioned definition ofring Z include similar groups to the substituent explained for theaforementioned definition “which may be substituted.” The position ofsubstituents existing on the hetero arene is not particularly limited,and when two or more substituents exist, they may be the same ordifferent.

Halogen atoms are preferred as the substituent in the definition of “ahetero arene which may have one or more substituents in addition to thegroup represented by formula —O-A wherein A has the same meaning as thatdefined above and the group represented by formula —X-E wherein each ofX and E has the same meaning as that defined above” in theaforementioned definition of ring Z.

Examples of the aryl group of “an aryl group which may be substituted”in the definition of E include similar groups to the aryl group in thedefinition of the aforementioned “hydrocarbon group,” and C₆ to C₁₀ arylgroups such as phenyl group, 1-naphthyl group, 2-naphthyl group and thelike are preferred, and phenyl group is most preferred.

Examples of the substituent in the definition of “an aryl group whichmay be substituted” in the definition of E include similar groups to thesubstituent explained for the definition “which may be substituted.” Theposition of substituents existing on the aryl group is not particularlylimited, and when two or more substituents exist, they may be the sameor different.

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a phenyl group which may be substituted,” “amono-substituted phenyl group,” “a di-substituted phenyl group,” and “aphenyl group which has three or more substituents” are preferred, and “adi-substituted phenyl group” is more preferred.

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a di-substituted phenyl group,” preferred examplesof the group include groups represented by the following SubstituentGroup δ-1e.

-   [Substituent Group δ-1e] 3,5-bis(trifluoromethyl)phenyl group,    3,4-propylenedioxyphenyl group, 3,5-dichlorophenyl group,    2,4-dihydroxyphenyl group, 2,5-dimethoxyphenyl group,    2-chloro-5-(trifluoromethyl)phenyl group,    3,5-bis[(1,1-dimethyl)ethyl]phenyl group,    2,5-bis(trifluoromethyl)phenyl group,    4-chloro-2-(trifluoromethyl)phenyl group,    2-fluoro-3-(trifluoromethyl)phenyl group,    4-fluoro-3-(trifluoromethyl)phenyl group,    4-chloro-3-(trifluoromethyl)phenyl group,    3-fluoro-5-(trifluoromethyl)phenyl group,    3-bromo-5-(trifluoromethyl)phenyl group,    2-fluoro-5-(trifluoromethyl)phenyl group,    4-nitro-3-(trifluoromethyl)phenyl group,    2-nitro-5-(trifluoromethyl)phenyl group,    4-cyano-3-(trifluoromethyl)phenyl group,    2-methyl-3-(trifluoromethyl)phenyl group,    4-methyl-3-(trifluoromethyl)phenyl group,    2-methyl-5-(trifluoromethyl)phenyl group,    4-methoxy-3-(trifluoromethyl)phenyl group,    3-methoxy-5-(trifluoromethyl)phenyl group,    2-methoxy-5-(trifluoromethyl)phenyl group,    2-methylsulfanyl-5-(trifluoromethyl)phenyl group,    2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,    2-morpholino-5-(trifluoromethyl)phenyl group,    2-chloro-4-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl group,    3,4-dichlorophenyl group, 3,5-difluorophenyl group,    3,5-dinitrophenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group,    5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 3,5-dimethylphenyl    group, 4-methoxybiphenyl-3-yl group, 3,5-dimethoxyphenyl group,    3,5-bis(methoxycarbonyl)phenyl group,    2-bromo-5-(trifluoromethyl)phenyl group,    3-methoxycarbonyl-5-(trifluoromethyl)phenyl group,    3-carboxy-5-(trifluoromethyl)phenyl group,    2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,    2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl    group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,    2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,    2-piperidino-5-(trifluoromethyl)phenyl group,    2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,    3,5-dicarboxyphenyl group, 5-isopropyl-2-methylphenyl group,    2,5-diethoxyphenyl group, 2,5-dimethylphenyl group, 5-chloro-2-cyano    group, 5-diethylsulfamoyl-2-methoxyphenyl group,    2-chloro-5-nitrophenyl group, 2-methoxy-5-(phenylcarbamoyl)phenyl    group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl    group, 2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group,    5-carbamoyl-2-methoxyphenyl group,    5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,    2-hexyloxy-5-methanesulfonyl group,    5-(2,2-dimethylpropionyl)-2-methylphenyl group,    5-methoxy-2-(1-pyrrolyl)phenyl group,    5-chloro-2-(p-toluenesulfonyl)phenyl group,    2-chloro-5-(p-toluenesulfonyl)phenyl group,    2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group,    4-methylbiphenyl-3-yl group,    2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group,    5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl    group, 2-butyl-5-nitrophenyl group,    5-[(1,1-dimethyl)]propyl-2-hydroxyphenyl group,    2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group,    4-isopropyl-2-(trifluoromethyl)phenyl group,    2-nitro-4-(trifluoromethyl)phenyl group,    4-bromo-3-(trifluoromethyl)phenyl group,    4-bromo-2-(trifluoromethyl)phenyl group,    2-bromo-4-(trifluoromethyl)phenyl group,    4-fluoro-2-(trifluoromethyl)phenyl group,    4-isopropoxy-2-(trifluoromethyl)phenyl group,    4-cyano-2-(trifluoromethyl)phenyl group, 2,6-diisopropylphenyl    group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group,    2,4-dichlorophenyl group, 2,3-dimethylphenyl group, indan-5-yl    group, 2,4-dimethylphenyl group, 2,6-dichlorophenyl group,    4-bromo-2-(trifluoromethoxy)phenyl group, 3,4-ethylenedioxyphenyl    group, 3-chloro-4-cyanophenyl group,    3-chloro-4-(trifluoromethoxy)phenyl group, 2-chloro-4-cyanophenyl    group, 2,3-dichlorophenyl group, 4-isopropyl-3-methylphenyl group,    4-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group,    3-chloro-2-cyanophenyl group, 2-cyano-4-methylphenyl group,    2,2-difluoro-1,3-benzodioxol-4-yl group,    2,2,3,3-tetrafluoro-1,4-benzodioxen-5-yl group,    3-chloro-4-(trifluoromethylsulfanyl)phenyl group,    2-nitro-4-(trifluoromethoxy)phenyl group,    2,2-difluoro-1,3-benzodioxol-5-yl group,    2-methyl-4-(trifluoromethoxy)phenyl group, 4-bromo-2-fluorophenyl    group, 2,4-bis(methanesulfonyl)phenyl group,    2,2,3,3-tetrafluoro-1,4-benzodioxen-6-yl group,    2-benzoyl-4-chlorophenyl group, 2-bromo-4-fluorophenyl group,    3,4-dimethoxyphenyl group, 3,4-difluorophenyl group,    3-chloro-4-methoxyphenyl group, 2-chloro-4-nitrophenyl group,    2,4-difluorophenyl group, 2-benzoyl-5-methylphenyl group,    2-bromo-4-(trifluoromethoxy)phenyl group, 3,4-dihexyloxyphenyl    group, 2,4-bis(trifluoromethyl)phenyl group,    4-cyano-2-(trifluoromethoxy)phenyl group,    2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and    2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a di-substituted phenyl group,” “a2,5-di-substituted phenyl group,” and “a 3,5-di-substituted phenylgroup” are preferred.

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a 2,5-di-substituted phenyl group,” preferredexamples of the group include groups represented by the followingSubstituent Group δ-2e.

-   [Substituent Group δ-2e] 2,5-dimethoxyphenyl group,    2-chloro-5-(trifluoromethyl)phenyl group,    2,5-bis(trifluoromethyl)phenyl group,    2-fluoro-5-(trifluoromethyl)phenyl group,    2-nitro-5-(trifluoromethyl)phenyl group,    2-methyl-5-(trifluoromethyl)phenyl group,    2-methoxy-5-(trifluoromethyl)phenyl group,    2-methylsulfanyl-5-(trifluoromethyl)phenyl group,    2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,    2-morpholino-5-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl    group, 2,5-bis[( 1,1-dimethyl)ethyl]phenyl group,    5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group,    4-methoxybiphenyl-3-yl group, 2-bromo-5-(trifluoromethyl)phenyl    group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,    2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl    group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,    2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,    2-piperidino-5-(trifluoromethyl)phenyl group,    2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,    5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group,    2,5-dimethylphenyl group, 5-chloro-2-cyano group,    5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-nitrophenyl    group, 2-methoxy-5-(phenylcarbamoyl)phenyl group,    5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl group,    2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group,    5-carbamoyl-2-methoxyphenyl group,    5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,    2-hexyloxy-5-methanesulfonyl group,    5-(2,2-dimethylpropionyl)-2-methylphenyl group,    5-methoxy-2-(1-pyrrolyl)phenyl group,    5-chloro-2-(p-toluenesulfonyl)phenyl group,    2-chloro-5-(p-toluenesulfonyl)phenyl group,    2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group,    2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group,    5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl    group, 2-butyl-5-nitrophenyl group,    5-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group,    2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group,    2-benzoyl-5-methylphenyl group,    2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and    2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a 2,5-di-substituted phenyl group,” “a2,5-di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group” is more preferred, a groupselected from the following Substituent Group δ-3e is further preferred,and 2,5-bis(trifluoromethyl)phenyl group is most preferred.

-   [Substituent Group δ-3e] 2-chloro-5-(trifluoromethyl)phenyl group,    2,5-bis(trifluoromethyl)phenyl group,    2-fluoro-5-(trifluoromethyl)phenyl group,    2-nitro-5-(trifluoromethyl)phenyl group,    2-methyl-5-(trifluoromethyl)phenyl group,    2-methoxy-5-(trifluoromethyl)phenyl group,    2-methylsulfanyl-5-(trifluoromethyl)phenyl group,    2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,    2-morpholino-5-(trifluoromethyl)phenyl group,    2-bromo-5-(trifluoromethyl)phenyl group,    2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,    2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl    group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,    2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,    2-piperidino-5-(trifluoromethyl)phenyl group,    2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and    2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a 3,5-di-substituted phenyl group,” preferredexamples of the group include groups represented by the followingSubstituent Group δ-4e.

-   [Substituent Group δ-4e] 3,5-bis(trifluoromethyl)phenyl group,    3,5-dichlorophenyl group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group,    3-fluoro-5-(trifluoromethyl)phenyl group,    3-bromo-5-(trifluoromethyl)phenyl group,    3-methoxy-5-(trifluoromethyl)phenyl group, 3,5-difluorophenyl group,    3,5-dinitrophenyl group, 3,5-dimethylphenyl group,    3,5-dimethoxyphenyl group, 3,5-bis(methoxycarbonyl)phenyl group,    3-methoxycarbonyl-5-(trifluoromethyl)phenyl group,    3-carboxy-5-(trifluoromethyl)phenyl group, and 3,5-dicarboxyphenyl    group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a 3,5-di-substituted phenyl group,” “a3,5-di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group” is more preferred, a groupselected from the following Substituent Group δ-5e is further preferred,and 3,5-bis(trifluoromethyl)phenyl group is most preferred.

-   [Substituent Group δ-5e] 3,5-bis(trifluoromethyl)phenyl group,    3-fluoro-5-(trifluoromethyl)phenyl group,    3-bromo-5-(trifluoromethyl)phenyl group,    3-methoxy-5-(trifluoromethyl)phenyl group,    3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and    3-carboxy-5-(trifluoromethyl)phenyl group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a mono-substituted phenyl group,” preferred examplesof the group include groups represented by the following SubstituentGroup δ-6e.

-   [Substituent Group δ-6e] 4-methoxyphenyl group, 4-chlorophenyl    group, 2-methoxyphenyl group, 2-(trifluoromethyl)phenyl group,    3-(trifluoromethyl)phenyl group, 4-(trifluoromethyl)phenyl group,    3-chlorophenyl group, biphenyl-3-yl group, 3-acetylphenyl group,    3-(acetylamino)phenyl group, 3-carbamoylphenyl group,    3-methylcarbomoylphenyl group, 4-methylphenyl group,    3-(trifluoromethoxy)phenyl group, 2-benzylphenyl group,    4-(trifluoromethoxy)phenyl group, 4-[(1,1-dimethyl)ethyl]phenyl    group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group,    4-hexylphenyl group, 3-methylphenyl group, 4-cyclohexylphenyl group,    4-benzylphenyl group, 2-chlorophenyl group, 2-methylphenyl group,    4-butylphenyl group, 4-benzyloxyphenyl group, 3-benzylphenyl group,    4-hexyloxyphenyl group, 3-isopropylphenyl group, 4-cyanophenyl    group, 3-cyanophenyl group, 4-(ethoxycarbonylmethyl)phenyl group,    3-(trifluoromethylsulfanyl)phenyl group,    4-(trifluoromethylsulfanyl)phenyl group,    4-(trifluoromethanesulfonyl)phenyl group, 3-ethynylphenyl group,    4-(1-methylpropyl)phenyl group, 3-benzoylphenyl group,    3-methoxyphenyl group, 4-(acetylamino)phenyl group,    4-sulfamoylphenyl group, 4-difluoromethoxy)phenyl group,    3-methylsulfanylphenyl group, 4-methanesulfonylphenyl group,    3-(butylsulfamoyl)phenyl group, 3-benzyloxyphenyl group,    4-(p-toluenesulfonylamino)phenyl group, 4-morpholinophenyl group,    3-[(1,1-dimethyl)ethyl]phenyl group, 3-(5-methylfuran-2-yl)phenyl    group, 3-sulfamoylphenyl group, 3-(trifluoromethanesulfonyl)phenyl    group, 3-hexyloxyphenyl group, 4-acetylphenyl group, biphenyl-2-yl    group, biphenyl-4-yl group,    3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group,    3-[5-[(1,1-dimethyl)ethyl]-3-(trifluoromethyl)pyrazol-1-yl)phenyl    group, 4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group,    3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group, and    4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a phenyl group which has three or moresubstituents,” preferred examples of the group include groupsrepresented by the following Substituent Group δ-7e.

-   [Substituent Group δ-7e] 3,5-bis(trifluoromethyl)-2-bromophenyl    group, 3,4,5-trichlorophenyl group, 3,5-dichloro-4-hydroxyphenyl    group, pentafluorophenyl group,    3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group,    3,5-bis(trifluoromethyl)-2-methylphenyl group,    2,6-dichloro-4-(trifluoromethyl)phenyl group,    2,4-dimethoxy-5-(trifluoromethyl)phenyl group,    2,4-difluoro-5-(trifluoromethyl)phenyl group,    4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl    group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group,    2,3-difluoro-4-(trifluoromethyl)phenyl group,    2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group,    2,4,6-trimethylphenyl group, 2-cyano-4,5-dimethoxyphenyl group,    2,4-dichloro-5-isopropoxyphenyl group, 2,3,5-trifluorophenyl group,    2,4,5-trichlorophenyl group, and 5-ethoxy-4-fluoro-2-nitrophenyl    group

When “an aryl group which may be substituted” in the aforementioneddefinition of E is “a naphthyl group which may be substituted,”preferred examples of the group include 1-naphthyl group,4-methoxynaphthalen-2-yl group, and 4-hydroxy-3-methylnaphthalen-1-ylgroup.

Examples of the “heteroaryl group” in “a heteroaryl group which may besubstituted” in the definition of E include similar groups to the“monocyclic heteroaryl group” and “fused polycyclic heteroaryl group” inthe definition of the aforementioned “heterocyclic group.” A 5 to13-membered heteroaryl group is preferred, and preferred examples of thegroup include thienyl group, pyrazolyl group, oxazolyl group,1,3,4-thiadiazolyl group, pyridyl group, pyrimidinyl group, indolylgroup, quinolyl group, carbazolyl group, thiazolyl group, and pyrazinylgroup.

A 5-membered heteroaryl group is more preferred as the “heteroarylgroup” in “a heteroaryl group which may be substituted” in thedefinition of E. Thienyl group, pyrazolyl group, oxazolyl group,1,3,4-thiadiazolyl group, and thiazolyl group are further preferred, andthiazolyl group is most preferred.

Examples of the substituent in the definition of “a heteroaryl groupwhich may be substituted” in the aforementioned definition of E includesimilar groups to the substituent explained for the definition “whichmay be substituted.” The position of substituents existing on theheteroaryl group is not particularly limited, and when two or moresubstituents exist, they may be the same or different.

When “a heteroaryl group which may be substituted” in the aforementioneddefinition of E is “a thiazolyl group which may be substituted,” “athiazol-2-yl group which may be substituted.” “A mono-substitutedthiazol-2-yl group” and “a di-substituted thiazol-2-yl group” are morepreferred, and “a di-substituted thiazol-2-yl group” is furtherpreferred.

When “a heteroaryl group which may be substituted” in the aforementioneddefinition of E is “a di-substituted thiazol-2-yl group,” a groupselected from the following Substituent Group δ-8e is preferred, and4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group ismost preferred.

-   [Substituent Group δ-8e] 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl    group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group,    5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,    5-methylthiazol-2-yl group, 4,5-dimethylthiazol-2-yl group,    5-methyl-4-phenylthiazol-2-yl group,    5-(4-fluorophenyl)-4-methylthiazol-2-yl group,    4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl group,    4-ethyl-5-phenylthiazol-2-yl group, 4-isopropyl-5-phenylthiazol-2-yl    group, 4-butyl-5-phenylthiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl    group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl    group,    4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl    group, 5-carboxymethyl-4-phenylthiazol-2-yl group,    4,5-diphenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl group,    5-phenyl-4-(trifluoromethyl)thiazol-2-yl group,    5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl    group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group,    5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group,    5-methylcarbamoyl-4-phenylthiazol-2-yl group,    5-ethylcarbamoyl-4-phenylthiazol-2-yl group,    5-isopropylcarbamoyl-4-phenylthiazol-2-yl group,    5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group,    5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group,    5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,    5-(ethoxycarbonyl)methyl-4-phenylthiazol-2-yl group,    5-carboxy-4-phenylthiazol-2-yl group, and    5-propylcarbamoyl-4-phenylthiazol-2-yl group.

When “a heteroaryl group which may be substituted” in the aforementioneddefinition of E is “a mono-substituted thiazol-2-yl group,” preferredexamples of the group include groups represented by the followingSubstituent Group δ-9e.

-   [Substituent Group δ-9e] 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,    4-phenylthiazol-2-yl group,    4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl group,    4-(2,4-dichlorophenyl)thiazol-2-yl group,    4-(3,4-dichlorophenyl)thiazol-2-yl group,    4-[4-(trifluoromethyl)phenyl]thiazol-2-yl group,    4-(2,5-difluorophenyl)thiazol-2-yl group,    4-(4-methoxyphenyl)thiazol-2-yl group,    4-[3-(trifluoromethyl)phenyl]thiazol-2-yl group, and    4-(pentafluorophenyl)thiazol-2-yl group

The compounds represented by the aforementioned general formula (I-1)are explained in details.

Examples of the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-acetoxyphenyl groupwhich may be substituted in the 5-position” in the definition of Z¹include similar groups to the substituent explained for the definition“which may be substituted.”

“2-Hydroxyphenyl group which is substituted in the 5-position” ispreferred as the “2-hydroxyphenyl group which may be substituted in the5-position” in the definition of Z¹.

Preferred examples of the substituent in the definition of“2-hydroxyphenyl group which may be substituted in the 5-position” and“2-hydroxyphenyl group which is substituted in the 5-position ” in thedefinition of Z¹ include a group selected from the following SubstituentGroup γ¹-1z. A halogen atom and tert-butyl group are more preferred, anda halogen atom is most preferred.

-   [Substituent Group γ¹-1z] a halogen atom, nitro group, cyano group,    methoxy group, methyl group, isopropyl group, tert-butyl group,    1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group,    2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl    group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group,    phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl    group, pentafluoroethyl group, phenyl group,    4-(trifluoromethyl)phenyl group, 4-fluorophenyl group,    2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group,    1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group,    2-thienyl group, 3-thienyl group, 1-pyrrolyl group,    2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group,    2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl    group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl    group, carboxy group, methoxycarbonyl group,    N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,    N,N-dimethylcarbamoyl group, sulfamoyl group,    N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,    N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,    acetylamino group, benzoylamino group, methanesulfonylamino group,    benzenesulfonylamino group, 3-phenylureido group,    (3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and    {[4-(pyridin-2-yl)sulfamoyl]phenyl} diazenyl group

“2-Acetoxyphenyl group which is substituted in the 5-position” ispreferred as the “2-acetoxyphenyl group which may be substituted in the5-position” in the definition of Z¹.

A halogen atom is preferred as the substituent in the definition of“2-acetoxyphenyl group which may be substituted in the 5-position” and“2-acetoxyphenyl group which is substituted in the 5-position” in thedefinition of Z¹.

The definition “which may be substituted” in the definition of “a phenylgroup which may be substituted” in the definition of E¹ has the samemeaning as “which may be substituted.”

Examples of the substituent in the definition of “a phenyl group whichmay be substituted” in the definition of E¹ include similar groups tothe substituents explained for the definition “which may besubstituted.” A position of a substituent existing on the phenyl groupis not particularly limited, and when two or more substituents exist,they may be the same or different.

Preferred examples of “a phenyl group which may be substituted” in thedefinition of E¹ include 3,5-bis(trifluoromethyl)phenyl group,2,5-bis(trifluoromethyl)phenyl group, a phenyl group which has three ormore substituents wherein at least one of said substituents istrifluoromethyl group, and a di-substituted phenyl group wherein atleast one of said substituents is trifluoromethyl group, (provided thata 2,5-di-substituted phenyl group and a 3,5-di-substituted phenyl groupare excluded as said di-substituted phenyl group.)3,5-Bis(trifluoromethyl)phenyl group and 2,5-bis(trifluoromethyl)phenylgroup are more preferred.

When “a phenyl group which may be substituted” in the definition of E¹is “a phenyl group which has three or more substituents wherein at leastone of said substituents is trifluoromethyl group,” preferred examplesof the group include groups represented by the following SubstituentGroup δ¹-1e.

-   [Substituent Group δ¹-1e] 3,5-bis(trifluoromethyl)-2-bromophenyl    group, 3,5-bis(trifluoromethyl)-2-methylphenyl group,    2,6-dichloro-4-(trifluoromethyl)phenyl group,    2,4-dimethoxy-5-(trifluoromethyl)phenyl group,    2,4-difluoro-5-(trifluoromethyl)phenyl group,    4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl    group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group,    2,3-difluoro-4-(trifluoromethyl)phenyl group, and    2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group

When “a phenyl group which may be substituted” in the definition of E¹is “a di-substituted phenyl group wherein at least one of saidsubstituents is trifluoromethyl group, (provided that a2,5-di-substituted phenyl group and a 3,5-di-substituted phenyl groupare excluded from said di-substituted phenyl group)” preferred examplesof the group include groups represented by the following SubstituentGroup δ¹-2e.

-   [Substituent Group δ¹-2e] 4-chloro-2-(trifluoromethyl)phenyl group,    2-fluoro-3-(trifluoromethyl)phenyl group,    4-fluoro-3-(trifluoromethyl)phenyl group,    4-chloro-3-(trifluoromethyl)phenyl group,    4-nitro-3-(trifluoromethyl)phenyl group,    4-cyano-3-(trifluoromethyl)phenyl group,    2-methyl-3-(trifluoromethyl)phenyl group,    4-methyl-3-(trifluoromethyl)phenyl group,    4-methoxy-3-(trifluoromethyl)phenyl group,    2-chloro-4-(trifluoromethyl)phenyl group,    4-isopropyl-2-(trifluoromethyl)phenyl group,    2-nitro-4-(trifluoromethyl)phenyl group,    4-bromo-3-(trifluoromethyl)phenyl group,    4-bromo-2-(trifluoromethyl)phenyl group,    2-bromo-4-(trifluoromethyl)phenyl group,    4-fluoro-2-(trifluoromethyl)phenyl group,    4-isopropoxy-2-(trifluoromethyl)phenyl group,    4-cyano-2-(trifluoromethyl)phenyl group, and    2,4-bis(trifluoromethyl)phenyl group

Compounds represented by the aforementioned general formula (I-2) areexplained in details.

Examples of the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-acetoxyphenyl groupwhich may be substituted in the 5-position” in the definition of Z²include similar groups to the substituent explained for the definition“which may be substituted.”

“2-Hydroxyphenyl group which is substituted in the 5-position” ispreferred as the “2-hydroxyphenyl group which may be substituted in the5-position” in the definition of Z₂.

A halogen atom, nitro group, methyl group, and methoxy group arepreferred as the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-hydroxyphenyl groupwhich is substituted in the 5-position” in the definition of Z², and ahalogen atom is most preferred.

“2-Acetoxyphenyl group which is substituted in the 5-position” ispreferred as the “2-acetoxyphenyl group which may be substituted in the5-position” in the definition of Z².

A halogen atom is preferred as the substituent in the definition of“2-acetoxyphenyl group which may be substituted in the 5-position” and“2-acetoxyphenyl group which is substituted in the 5-position” in thedefinition of Z².

Examples of the substituent in the definition of “a 2,5-di-substitutedphenyl group wherein one of said substituents is trifluoromethyl group”and “a 3,5-di-substituted phenyl group wherein one of said substituentsis trifluoromethyl group” in the definition of E² include similar groupsto the substituent explained for the definition “which may besubstituted.”

A group selected from the following Substituent Group δ²-1e is preferredas “a 2,5-di-substituted phenyl group wherein one of said substituentsis trifluoromethyl group” in the definition of E².

-   [Substituent Group δ²-1e] 2-chloro-5-(trifluoromethyl)phenyl group,    2,5-bis(trifluoromethyl)phenyl group,    2-fluoro-5-(trifluoromethyl)phenyl group,    2-nitro-5-(trifluoromethyl)phenyl group,    2-methyl-5-(trifluoromethyl)phenyl group,    2-methoxy-5-(trifluoromethyl)phenyl group,    2-methylsulfanyl-5-(trifluoromethyl)phenyl group,    2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,    2-morpholino-5-(trifluoromethyl)phenyl group,    2-bromo-5-(trifluoromethyl)phenyl group,    2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,    2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl    group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,    2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,    2-piperidino-5-(trifluoromethyl)phenyl group,    2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,    2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and    2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group

A group selected from the following Substituent Group δ²-2e is preferredas “a 3,5-di-substituted phenyl group wherein one of said substituentsis trifluoromethyl group” in the definition of E².

-   [Substituent Group δ²-2e] 3,5-bis(trifluoromethyl)phenyl group,    3-fluoro-5-(trifluoromethyl)phenyl group,    3-bromo-5-(trifluoromethyl)phenyl group,    3-methoxy-5-(trifluoromethyl)phenyl group,    3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and    3-carboxy-5-(trifluoromethyl)phenyl group

Compounds represented by the aforementioned general formula (I-3) areexplained in details.

Examples of the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-acetoxyphenyl groupwhich may be substituted in the 5-position” in the definition of Z³include similar groups to the substituent explained for the definition“which may be substituted.”

“2-Hydroxyphenyl group which is substituted in the 5-position” ispreferred as the “2-hydroxyphenyl group which may be substituted in the5-position” in the definition of Z³.

A halogen atom, nitro group, methyl group and methoxy group arepreferred as the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-hydroxyphenyl groupwhich is substituted in the 5-position” in the definition of Z³, and ahalogen atom is most preferred.

“2-Acetoxyphenyl group which is substituted in the 5-position” ispreferred as the “2-acetoxyphenyl group which may be substituted in the5-position” in the definition of Z³.

A halogen atom is preferred as the substituent in the definition of“2-acetoxyphenyl group which may be substituted in the 5-position” and“2-acetoxyphenyl group which is substituted in the 5-position” in thedefinition of Z³.

Examples of the substituent in the definition of “a hydrocarbon groupwhich may be substituted” in the definition of R^(3e2) and R^(3e3) and“a C₂ to C₆ hydrocarbon group which may be substituted” in thedefinition of R^(3e5) include similar groups to the substituentexplained for the definition “which may be substituted.”

Examples of the “hydrocarbon group” in the definition of “a hydrocarbongroup which may be substituted” in the definition of R^(3e2) and R^(3e3)and “a C₂ to C₆ hydrocarbon group which may be substituted” in thedefinition of R^(3e5) include similar groups to the “hydrocarbon group”in the aforementioned definition.

Examples of the “hydroxy group which may be substituted” in thedefinition of R^(3e2) and R^(3e3) include similar groups to the “hydroxygroup which may be substituted” explained for the definition “which maybe substituted.”

As E³, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group,2,5-bis[(1,1-dimethyl)ethyl]phenyl group,5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 4-methoxybiphenyl-3-ylgroup, 5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,4-methylbiphenyl-3-yl group and 5-[(1,1-dimethyl)propyl]-2-hydroxyphenylgroup are preferred, and 3,5-bis[(1,1-dimethyl)ethyl]phenyl group ismore preferred.

Compounds represented by the aforementioned general formula (I-4) areexplained in details.

Examples of the substituent in the definition of “2-hydroxyphenyl groupwhich may be substituted in the 5-position” and “2-acetoxyphenyl groupwhich may be substituted in the 5-position” in the definition of Z⁴include similar groups to the substituent explained for the definition“which may be substituted.”

“2-Hydroxyphenyl group which is substituted in the 5-position” ispreferred as the “2-hydroxyphenyl group which may be substituted in the5-position” in the definition of Z⁴.

A halogen atom, phenyl group, 4-fluorophenyl group, 2,4-difluorophenylgroup, 4-(trifluoromethyl)phenyl group, 1-pyrrolyl group and 2-thienylgroup are preferred as the substituent in the definition of“2-hydroxyphenyl group which may be substituted in the 5-position” and“2-hydroxyphenyl group which is substituted in the 5-position” in thedefinition of Z⁴, and a halogen atom is most preferred.

“2-Acetoxyphenyl group which is substituted in the 5-position” ispreferred as the “2-acetoxyphenyl group which may be substituted in the5-position” in the definition of Z⁴.

A halogen atom is preferred as the substituent in the definition of“2-acetoxyphenyl group which may be substituted in the 5-position” and“2-acetoxyphenyl group which is substituted in the 5-position” in thedefinition of Z⁴.

Examples of the substituent in the definition of “a hydrocarbon groupwhich may be substituted” in the definition of R^(4e4), and “an acylgroup which may be substituted” and “a heterocyclic group which may besubstituted” in the definition of R^(4e5) include similar groups to thesubstituent explained for the definition “which may be substituted.”

Examples of the “hydrocarbon group” in the definition of “a hydrocarbongroup which may be substituted” in the definition of R^(4e4) includesimilar groups to the “hydrocarbon group” in the aforementioneddefinition.

Examples of the “acyl group” in the definition of “an acyl group whichmay be substituted” in the definition of R^(4e5) include similar groupsto the “acyl group” in the aforementioned definition.

Examples of the “heterocyclic group” in the definition of “aheterocyclic group which may be substituted” in the definition ofR^(4e5) include similar groups to the “heterocyclic group” in theaforementioned definition.

A group selected from the following Substituent Group δ⁴-1e is preferredas E⁴, and4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group ismost preferred.

-   [Substituent Group δ-1e] 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl    group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl group,    5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,    5-methylthiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl    group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group,    4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl    group,    4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl    group, 5-carboxymethyl-4-phenylthiazol-2-yl group,    5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl    group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group,    5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group,    5-methylcarbamoyl-4-phenylthiazol-2-yl group,    5-ethylcarbamoyl-4-phenylthiazol-2-yl group,    5-isopropylcarbamoyl-4-phenylthiazol-2-yl group,    5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group,    5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group,    5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,    5-carboxy-4-phenylthiazol-2-yl group, and    5-propylcarbamoyl-4-phenylthiazol-2-yl group.

Among the compound represented by the general formulas (I), (I-1),(1-2), (I-3) and (I-4), preferred compounds are those other than“substituted benzoic acid derivatives represented by the followinggeneral formula (X-1) and/or compounds represented by the followingCompound Group φ-1.”

-   wherein R¹⁰⁰¹ represents the following general formula (X-2):-   or the following general formula (X-3):-   wherein each of R¹⁰⁰³, R¹⁰⁰⁴ and R¹⁰⁰⁵ independently represents    hydrogen atom, an alkyl group having from 1 to 6 carbons or an    alkoxy group having from 1 to 6 carbons, each of R¹⁰⁰⁹ and R¹⁰¹⁰    independently represents hydrogen atom, an alkyl group having from 1    to 6 carbons, or an acyl group having from 2 to 11 carbons;-   R¹⁰⁰² represents hydrogen atom, a lower alkyl group having from 1 to    6 carbons, which may be substituted, an aryl group having from 6 to    12 carbons, which may be substituted, a heteroaryl group having from    4 to 11 carbons, which may be substituted, an aralkyl group having    from 7 to 14 carbons, which may be substituted, a heteroarylalkyl    group having from 5 to 13 carbons, which may be substituted, or an    acyl group having from 2 to 11 carbons;-   X¹⁰⁰¹ represents carboxy group which may be esterified or amidated.

Each compound defined by the aforementioned general formulas (I-1),(I-2), (I-3), and (I-4), or a pharmacologically acceptable salt thereof,or a hydrate thereof or a solvate thereof is novel. Uses of the compoundaccording to the aforementioned chemical substance invention are notparticularly limited.

The compounds represented by the aforementioned general formulas (I),(I-1), (I-2), (I-3) and (1-4) may form salts. Examples ofpharmacologically acceptable salts include, when acidic groups exist,metal salts such as lithium salt, sodium salt, potassium salt, magnesiumsalt, calcium salts, or ammonium salts such as ammonium salt,methylammonium salt, dimethylammonium salt, trimethylammonium salt,dicyclohexylammonium salt, and when basic groups exist, mineral acidsalts such as hydrochloride, oxalate, hydrosulfate, nitrate, phosphate,or organic acid salts such as methane sulfonate, benzene sulfonate,para-toluene sulfonate, acetate, propionate, tartrate, fumarate,maleate, malate, oxalate, succinate, citrate, benzoate, mandelate,cinnamate, lactate. Salts may sometimes be formed with amino acids suchas glycine. As active ingredients of the medicament of the presentinvention, pharmacologically acceptable salts may also be suitably used.

The compounds or salts thereof represented by the aforementioned generalformulas (I), (I-1), (I-2), (1-3) and (1-4) may exist as hydrates orsolvates. As active ingredients of the medicament of the presentinvention, any of the aforementioned substances may be used.Furthermore, the compounds represented by the aforementioned generalformulas (I), (I-1), (I-2), (I-3) and (I-4) may sometimes have one ormore asymmetric carbons, and may exist as steric isomers such asoptically active substance and diastereomer. As active ingredients ofthe medicament of the present invention, pure forms of stereoisomers,arbitrary mixture of enantiomers or diastereomers, and racemates may beused.

Furthermore, when the compounds represented by the general formulas (I),(I-1), (I-2), (1-3) and (I-4) has, for example, 2-hydroxypyridine form,the compounds may exist as 2-pyridone form which is a tautomer. Asactive ingredients of the medicament of the present invention, pureforms of tautomers or a mixture thereof may be used. When the compoundsrepresented by the general formulas (I), (I-1), (I-2), (I-3) and (I-4)have olefinic double bonds, the configuration may be in either E or Z,and as active ingredients of the medicament of the present invention,geometrical isomer in either of the configurations or a mixture thereofmay be used.

Examples of the compounds included in the general formulas (I), (I-1),(I-2), (I-3) and (I-4) as active ingredients of the medicaments of thepresent invention are shown below. However, the active ingredients ofthe medicaments of the present invention are not limited to the compoundset out below.

The abbreviations used in the following tables have the followingmeanings.

Me: methyl group, Et: ethyl group.

     Compound Number

      X       E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

      Compound Number

      E 18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

     Compound Number

      X       E 301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

      Compound Number

      E 322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

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     Compound Number

      X       E 553

554

555

Methods for preparation of the compounds represented by the generalformulas (I), (I-1), (I-2), (I-3) and (I-4) are not particularlylimited. Reference to methods described in the pamphlet of InternationalPublication WO02/49632 is useful.

The compounds represented by the general formulas (I), (I-1), (I-2),(I-3) and (I-4) can be prepared, for example, by methods shown bellow.

<Method 1>

The compounds represented by the general formula (I), wherein X is—CONH— (the hydrogen atom on the nitrogen may be substituted) and thecompounds represented by the general formulas (I-1), (I-2), (I-3) and(I-4) can be prepared, for example, by a method described in thereaction scheme 1.

wherein each of A, ring Z, and E has the same meaning as that defined inthe general formula (I), A¹⁰¹ represents a hydrogen atom or protectinggroups of hydroxy group (preferably, an alkyl group such as methyl groupand the like; an aralkyl group such as benzyl group and the like; anacetyl group, an alkoxyalkyl group such as methoxymethyl group and thelike; a substituted silyl group such as trimethylsilyl group or thelike), each of R and R¹⁰¹ represents a hydrogen atom, a C₁ to C₆ alkylgroup or the like, E¹⁰¹ represents E or precursor of E in the definitionof the general formula (I), G represents a hydroxy group, halogen atoms(preferably, a chlorine atom), a hydrocarbon-oxy group (preferably, anaryl-oxy group which may be substituted by halogen atom), an acyl-oxygroup, an imido-oxy group or the like.(First Step)

The amide (3) can be prepared by dehydrocondensation of the carboxylicacid derivative (1) and the amine (2). This reaction is carried out at areaction temperature of from 0° C. to 180° C., without solvent or in anaprotic solvent, in the presence of an acid halogenating agent or adehydrocondensing agent, and in the presence or absence of a base.

As the halogenating agent, examples include, for example, thionylchloride, thionyl bromide, sulfuryl chloride, phosphorus oxychloride,phosphorus trichloride, phosphorus pentachloride or the like. When A¹⁰¹is hydrogen atom, phosphorus trichloride is preferable, and when A¹⁰¹ isacetyl group or the like, phosphorus oxychloride is preferable. As thedehydrocondensing agent, examples include, for example,N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,diphenylphosphorylazide or the like. As the base, examples includeinorganic bases such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate or the like, or organic bases such as pyridine,triethylamine, N,N′-diethylaniline or the like. As the aprotic solvent,examples include dichloromethane, dichloroethane, chloroform,tetrahydrofuran, 1,4-dioxane, benzene, toluene, monochlorobenzene,o-dichlorobenzene, N,N′-dimethylformamide, N-methylpyrrolidone or thelike, when the reaction is carried out in the presence of the acidhalogenating agent, particularly, toluene, monochlorobenzene,o-dichlorobenzene are preferable.

A target compound can also be prepared, for example, by a method orsimilar method described in Journal of Medicinal Chemistry, (USA), 1998,Vol. 41, No. 16, p. 2939-2945, in which the acid chloride is preparedand isolated beforehand from carboxylic acid, then the result is made toreact with an amine having E¹⁰¹.

When G is hydroxy group, the reaction condition described in Archiv derPharmazie, (Germany), 1998, Vol. 331, No. 1, p. 3-6 can be used as apreferred reaction condition.

Kinds of carboxylic acid derivative (1) and amine (2) are notparticularly limited, and new compounds synthesized by referring towell-known preparation method described in the literature orcommercially available reagents can be used for the aforementionedreaction.

(Second Step)

When the amide (3) has a protecting group and/or has a favorablesubstituent for functional group modification, for example, an aminogroup and a protected amino group or its precursor; a carboxy group anda protected carboxy group or its precursor; a hydroxy group and aprotected hydroxy group or its precursor, the final target compound (4)can be prepared by a reaction for deprotection and/or functional groupmodification in this step. Various well-known methods can be used forthe reaction. For the reaction of deprotection and functional groupmodification, for example, methods described in “Protective Groups inOrganic Syntheses”, (USA), Theodra W. Green, Peter G. M. Wuts, Eds.,Third edition, April in 1999, John Wiley & Sons, and “Handbook ofReagents for Organic Synthesis”, (USA), 4 Volumes, June in 1999, JohnWiley & Sons can be used, and for the reaction of functional groupmodification, for example, methods described in “Palladium Reagents inOrganic Syntheses”, (USA), Richard F. Heck, 1985, Academic Press, and“Palladium Reagents and Catalysts: Innovations in Organic Synthesis”,(USA), J. Tsuji, 1999, John Wiley & Sons, or the like can be used.

The aforementioned methods are applicable by appropriately combining rawmaterials even for the compounds wherein X is other connecting group,for example, —SO₂NH—, —NHCO—, —NHSO₂—, —CONHCH₂—, —CONHCH₂CH₂—,—CONHCH₂CONH—, —CONHNHCO—, —CONHNHCH₂—, —COO—, —CONHNH—; wherein thehydrogen atom on said connecting group may be substituted.

In the general formula (I), when X is the formula: —CONHCH₂— wherein thehydrogen atom on said connecting group may be substituted, the targetcompound can be prepared by using an amine represented by the formula:H₂N—CH₂-E¹⁰¹, wherein E¹⁰¹ has the same meaning as that defined above,instead of the amine (2).

In the general formula (I), when X is the formula: —CONHCH₂CH₂— whereinthe hydrogen atom on said connecting group may be substituted, thetarget compound can be prepared by using an amine represented by theformula: H₂N—CH₂ CH₂-E¹⁰¹, wherein E¹⁰¹ has the same meaning as thatdefined above, instead of the amine (2).

In the general formula (I), when X is the formula: —SO₂NH—, the targetcompound can be prepared by using a sulfonyl chloride represented by theformula: A¹⁰¹-O-(ring Z)-SO₂Cl, wherein each of A¹⁰¹ and ring Z has thesame meaning as that defined above, instead of the carboxylic acidderivative (1).

In the general formula (I), when X is the formula: —NHCO—, the targetcompound can be prepared by using an amine represented by the formula:A¹⁰¹-O-(ring Z)-NH₂, wherein each of A¹⁰¹ and ring Z has the samemeaning as that defined above, and a carboxylic acid represented by theformula: E¹⁰¹-COOH, wherein -E¹⁰¹ has the same meaning as that definedabove, or a carboxylic acid chloride represented by the formula:E¹⁰¹-COCl, wherein -E¹⁰¹ has the same meaning as that defined above.

In the general formula (I), when X is the formula: —NHSO₂—, wherein saidconnecting group may be substituted, the target compound can be preparedby using an amine represented by the formula: HO-(ring Z)-NH₂, whereinring Z has the same meaning as that defined above, and a sulfonylchloride represented by the formula: E¹⁰¹-SO₂Cl, wherein E¹⁰¹ has thesame meaning as that defined above.

In the general formula (I), when X is the formula: —CONHNHCO—, thetarget compound can be prepared by using a hydrazide represented by theformula: HO-(ring Z)-CONHNH₂, wherein ring Z has the same meaning asthat defined above, and a carboxylic acid chloride represented by theformula: E¹⁰¹-COCl, wherein -E¹⁰¹ has the same meaning as that definedabove.

In the general formula (I), when X is the formula: —COO—, the targetcompound can be prepared by using a phenol derivative represented by theformula: HO-E¹⁰¹, wherein -E¹⁰¹ has the same meaning as that definedabove, instead of the amine (2).

In the general formula (I), when X is the formula: —CONHNH—, the targetcompound can be prepared by using a hydrazine represented by theformula: H₂N—NH-E¹⁰¹ , wherein E¹⁰¹ has the same meaning as that definedabove, instead of the amine (2).

In the general formula (I), when X is the formula: —CONHCH₂CONH—, thetarget compound can be prepared by using an amine represented by theformula: H₂N—CH₂CONH-E¹⁰¹, wherein E¹⁰¹ has the same meaning as thatdefined above, instead of the amine (2).

The amine represented by the formula: H₂N—CH₂CONH-E¹⁰¹, can be prepared,for example, by condensation of the amine (2) and a N-protected aminoacid (for example, N-(tert-butoxycarbonyl)glycine), according to theaforementioned method 1, followed by a deprotection reaction.

In the general formula (I), when X is the following formula:

wherein said connecting group may be substituted, the target compoundcan be prepared by using an amine represented by the following formula:

wherein ring Z has the same meaning as that defined above, and acarboxylic acid represented by the formula: E¹⁰¹-COOH, wherein E¹⁰¹ hasthe same meaning as that defined above, or a carboxylic acid chloriderepresented by the formula: E¹⁰¹-COCl, wherein E¹⁰¹ has the same meaningas that defined above.

The amine represented by the following formula:

can be prepared, for example, by a method described in the reactionscheme 1-2.

wherein ring Z has the same meaning as that defined above.

The bromoacetophenone (20) can be prepared by bromination of theacetophenone (19).

This reaction is carried out at a reaction temperature of from 0° C. to100° C. in a solvent, in the presence of a brominating agent.

As the brominating agent, for example, phenyltrimethylammoniumtribromide can preferably be used.

As the reaction solvent, any solvent can be used as long as it does notinhibit the reaction, for example, ethers such as tetrahydrofuran can beused.

The amine (21) can be prepared by reacting the bromoacetophenone (20)with thiourea.

This reaction is carried out at a reaction temperature of from 0° C. to120° C. in a solvent.

As the reaction solvent, any solvent can be used as long as it does notinhibit the reaction, for example, alcohols such as ethanol can be used.

<Method 2>

The compounds represented by the general formula (I), wherein X is—CH₂NH— can be prepared, for example, by a method described in thereaction scheme 2.

wherein each of A, ring Z, and E has the same meaning as that defined inthe general formula (I).

The imine derivative of the formula (7) can be prepared bydehydrocondensation of the aldehyde (5) and the amine (6). This reactionis carried out at a reaction temperature of from 0° C. to 100° C. in asolvent, in the presence or absence of a dehydrating agent. As thedehydrating agent, examples include anhydrous magnesium sulfate,molecular sieves or the like. As the solvent, examples include inertsolvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the likeare preferable.

The aforementioned methods are applicable by appropriately combining rawmaterials even for the compounds wherein X is other connecting group,for example, —CONHN═CH—, —CH═NNHCO—, —CHNNH—; wherein the hydrogen atomon said connecting group may be substituted.

In the general formula (I), when X is the formula: —CONHN═CH—, thetarget compound can be prepared by using a hydrazide represented by theformula: HO-(ring Z)-CONHNH₂, wherein ring Z has the same meaning asthat defined above, and an aldehyde represented by the formula: E-CHO,wherein E has the same meaning as that defined above.

In the general formula (I), when X is the formula: —CH═NNHCO—, thetarget compound can be prepared by using an aldehyde represented by theformula: HO-(ring Z)-CHO, wherein ring Z has the same meaning as thatdefined above, and a hydrazide represented by the formula: E-CONHNH₂,wherein E has the same meaning as that defined above.

In the general formula (I), when X is the formula: —CH═NNH—, the targetcompound can be prepared by using an aldehyde represented by theformula: HO-(ring Z)-CHO, wherein ring Z has the same meaning as thatdefined above, and a hydrazine represented by the formula: E-NHNH₂,wherein E has the same meaning as that defined above.

The target compound (8) can be prepared by reduction of the iminederivative (7). This reaction is carried out at a reaction temperatureof from 0° C. to 100° C. in a solvent, in the presence of a reducingagent. As the reducing agent, examples include sodium borohydride,lithium borohydride or the like. As the solvent, examples include inertsolvent, and tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the likeare preferable. This reaction can also be carried out by a method ofcatalytic hydrogenation. As the catalyst, examples include palladiumcarbon, platinum carbon, palladium hydroxide, palladium black or thelike. As solvent, examples include inert solvent, and tetrahydrofuran,1,4-dioxane, methanol, ethanol or the like are preferable. The reactionis carried out at a reaction temperature of from 0° C. to 200° C., andthe hydrogen pressure may be an ordinary pressure or a positivepressure.

<Method 3>

The compounds represented by the general formula (I), wherein X is—CH═CH— (the hydrogen atom on said connecting group may be substituted),can be prepared, for example, by methods described in the reactionscheme 3-1 or the reaction scheme 3-2.

wherein each of ring Z and E has the same meaning as that defined in thegeneral formula (I), W³⁰¹ represents O,O′-di-hydrocarbon-phosphono groupor triarylphosphonium group

The target compound (11) can be prepared by dehydrocondensation of thealdehyde (9-1) and the phosphorus compound (10-1). This reaction iscarried out in a solvent at a reaction temperature of from 0° C. to theboiling point of the solvent, in the presence of a base. As the base,examples include inorganic base such as sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate or the like, or organic base such aspyridine, triethylamine, N,N-diethylaniline or the like. As the solvent,examples include inert solvent, and tetrahydrofuran, 1,4-dioxane,methanol, ethanol, water or the like are preferable.

wherein each of ring Z and E has the same meaning as that defined in thegeneral formula (I), W³⁰² represents halogen atoms (preferably, iodineatom and bromine atom), (trifluoromethanesulfonyl)oxy group and thelike.

The target compound (11) can be prepared by reacting the halogenatedcompound (9-2) with the styrene compound (10-2) in the presence of atransition-metal complex catalyst. This reaction is carried out in asolvent at a reaction temperature of from 0° C. to the boiling point ofthe solvent, in the presence or absence of a ligand and/or a base. Asthe transition-metal complex catalyst, examples include palladiumcatalyst such as palladium acetate anddichlorobis(triphenylphosphine)palladium. As the ligand, examplesinclude phosphine ligand such as triphenylphosphine. As the base,examples include inorganic base such as sodium carbonate, potassiumcarbonate, and sodium hydrogen carbonate, or organic base such aspyridine, triethylamine, and N,N-diethylaniline. As the solvent,examples include inert solvents, and N,N-dimethylformamide,tetrahydrofuran, 1,4-dioxane or the like are preferable.

<Method 4>

The compounds represented by the general formula (I), wherein X is—COCH═CH— and —COCH₂CH₂— (the hydrogen atom on said connecting group maybe substituted), can be prepared, for example, by a method described inthe reaction scheme 4.

wherein each of rings Z and E has the same meaning as that defined inthe general formula (I).

The target compound enone (14) can be prepared by dehydrocondensation ofthe ketone (12) and the aldehyde (13). This reaction is carried out in asolvent at a reaction temperature of from 0° C. to the boiling point ofthe solvent, in the presence of a base. As the base, examples includeinorganic base such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate or the like, ororganic base such as pyridine, triethylamine, N,N-diethylaniline or thelike. Examples include inert solvent, and tetrahydrofuran, 1,4-dioxane,methanol, ethanol, water or the like are preferable.

Next, the target compound (15) can be prepared by reduction of the enone(14). This reaction is carried out at a reaction temperature of from 0°C. to 100° C. in solvent, in the presence of a reducing agent. As thereducing agent, examples include sodium borohydride, lithium borohydrideor the like. As the solvent, examples include inert solvent, andtetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like arepreferable. Moreover, this reaction is carried out by a method ofcatalytic hydrogenation also. As the catalyst, examples includepalladium carbon, platinum carbon, palladium hydroxide, palladium blackor the like. As solvent, examples include inert solvent, andtetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like arepreferable. The reaction is carried out at a reaction temperature offrom 0° C. to 200° C., and the hydrogen pressure is at normal pressureor applied pressure.

<Method 5>

The compounds represented by the general formula (I), wherein X is—NHCONH— (the hydrogen atom on said connecting group may besubstituted), can be prepared, for example, by a method described in thereaction scheme 5.

wherein each of ring Z and E has the same meaning as that defined in thegeneral formula (I).

First, the target compound urea (18) can be prepared by reacting theamine (16) with the isocyanate (17). This reaction is carried out in asolvent at a reaction temperature of from 0° C. to the boiling point ofthe solvent, in the presence or absence of a base. As the base, examplesinclude inorganic base such as sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate or thelike, or organic base such as pyridine, triethylamine,N,N-diethylaniline or the like. Examples include inert solvent, andtetrahydrofuran, 1,4-dioxane, methanol, ethanol, water or the like arepreferable.

<Method 6>

The compounds represented by the general formula (I), wherein X is theformula: —CONHNHCH₂— (the hydrogen atom on said connecting group may besubstituted), can be prepared, for example, by a method described in thereaction scheme 6.

wherein each of ring Z and E has the same meaning as that defined above,and V represents a leaving group such as halogen atom.

The target compound hydrazide (24) can be prepared by reacting thehydrazide (22) with the benzyl derivative (23).

This reaction is carried out at a reaction temperature of from 0° C. to180° C. in a solvent, in the presence or absence of a base.

As the base, for example, organic base such as pyridine, triethylamineor the like can preferably be used.

As the reaction solvent, any solvent can be used as long as it does notinhibit the reaction, for example, halogenated solvent such asdichloromethane; ethers such as tetrahydrofuran; and hydrocarbon solventsuch as toluene can be used.

<Method 7>

The compounds represented by the general formula (I), wherein X is theformula:

can be prepared, for example, by a method described in the reactionscheme 7.

wherein each of ring Z and E has the same meaning as that defined above.

The target compound 5-(benzylidene)-3-benzylthiazolidin-2,4-dionederivative (26) can be prepared by reacting the aldehyde (9-1) with the3-benzylthiazolidin-2,4-dione derivative (25).

This reaction is carried out at a reaction temperature of from 0° C. to180° C. in a solvent, in the presence of a catalyst. As the catalyst,for example, a mixture of piperidine/acetic acid can preferably be used.As the reaction solvent, any solvent can be used as long as it does notinhibit the reaction, for example, hydrocarbon solvent such as toluenecan be used.

The 3-benzylthiazolidine-2,4-dione derivative represented by thefollowing formula:

wherein E has the same meaning as that defined above, can be prepared,for example, by a method described in the reaction scheme 7-1.

wherein each of E and V has the same meaning as that defined above.

The target compound 3-benzylthiazolidine-2,4-dione derivative (28) canbe prepared by reacting thiazolidine-2,4-dione (30) with the benzylderivative (23).

This reaction is carried out at a reaction temperature of from 0° C. to180° C. in a solvent, in the presence of a base. As the base, forexample, inorganic base such as sodium hydroxide, potassium carbonate orthe like, or organic base such as pyridine, triethylamine or the likecan preferably be used.

As the reaction solvent, any solvent can be used as long as it does notinhibit the reaction, for example, water; alcohols such as ethanol orthe like; halogenated solvent such as dichloromethane or the like;ethers such as tetrahydrofuran or the like; or amides such asN,N-dimethylformamide or the like can be used.

The compounds represented by the general formulas (I), (I-1), (I-2),(I-3) and (I-4) prepared by the aforementioned methods can be isolatedand purified by methods widely known by those skilled in the art, forexample, extraction, precipitation, fractional chromatography,fractional crystallization, suspension and washing, andrecrystallization. Furthermore, each of the pharmaceutically acceptablesalt of the compound of the present invention, the hydrate thereof andthe solvate thereof can be prepared by methods widely known by thoseskilled in the art.

In the examples of the specification, preparation methods of typicalcompounds included in the general formulas (I), (I-1), (I-2), (I-3) and(I-4) are explained in details. Therefore, those skilled in the art canprepare any compound fall within the general formulas (I), (I-1), (I-2),(I-3) and (I-4) by referring to the explanations of the aforementionedgeneral preparation methods and those of specific preparation methods ofthe examples, by choosing appropriate reaction raw materials, reactionreagents, and reaction conditions, and by adding appropriatemodification and alteration of these methods, if necessary.

The compounds represented by the general formulas (I), (I-1), (I-2),(I-3), and (I-4) have antiallergic action, and accordingly, they areuseful as active ingredients of the medicaments for the preventiveand/or therapeutic treatment of allergic diseases. The aforementionedmedicaments have inhibitory activity against the proliferation of mastcells, inhibitory activity against the production of IgE from activatedB cells, and inhibitory activity against the degranulation fromactivated mast cells. Therefore, they can be suitably used as asuppressant against allergic reaction expression. More specifically, themedicaments of the present invention are useful for the preventiveand/or therapeutic treatment of the following diseases wherein allergicreaction is believed to be involved, for example, allergic diseases suchas contact dermatitis, atopic dermatitis, eczema, pruritus, pollinosis,asthma, bronchitis, urticaria, vasculitis, rhinitis, gastrointestinalsymptoms, diarrhea, interstitial pneumonia, arthritis, ophthalmia,conjunctivitis, neuritis, otitis media, granulomatosis,encephalomyelitis, cystitis, laryngitis, peliosis, food allergy, insectallergy, drug allergy, metal allergy, anaphylactic shock and the like,and/or endometriosis and/or hysteromyoma.

Furthermore, in endometriosis, it is known that an adhesion of theuterus with its peripheral tissue frequently occurs due to an abnormalproliferation of endometrial tissue outside the uterus. It is known thatthis is caused by an inflammatory reaction by allergy and the like, anda phenomenon called as “remodeling” including fibrosis and hyperplasiaof tissue as typical examples occurs (Frontiers in Bioscience, (USA),2002, Vol. 7, the April 1 issue, p.e 91-115). As for the fibrosis oftissue, it is widely known that one of the causes is a production of alarge amount of collagen, which is triggered by infiltration of effectercells and activation of proliferation of fibroblast by inflammation.This remodeling phenomenon is considered to be occurred on the basis ofa mechanism common in the remodeling of cardiac muscle after myocardialinfarction, the remodeling of a vessel by arteriosclerosis, theremodeling of bronchus by bronchial asthma or the like, as well as inthe adhesion of a tissue in endometriosis. Accordingly, an inhibitoragainst the proliferation or activation of a fibroblast is considered tobe useful as a therapeutic drug not only for endometriosis but fordiseases in which fibrosis or remodeling of a tissue is believed to beinvolved, for example, myocardial infarction, arteriosclerosis, asthma,nephritis, interstitial pneumonia, pulmonary fibrosis, hepatic cirrhosisand the like.

The compounds of the present invention was found to inhibit cellproliferation of HT-1080, which is a fibrosarcoma cell having propertiessimilar to those of fibroblast and collagen productivity, underproliferative stimulation by PDGF (platelet-derived growth factor).Therefore, they are considered to be useful as a therapeutic drug and/ora preventive drug for diseases in which fibrosis or remodeling of tissueis involved.

As the active ingredient of the medicament on the present invention, oneor more kinds of substances selected from the group consisting of thecompound represented by the general formulas (I), (I-1), (I-2), (I-3)and (I-4) and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof may be used. The aforementioned substance,per se, may be administered as the medicament of the present invention,however, preferably, the medicament of the present invention is providedin the form of a pharmaceutical composition comprising theaforementioned substance which is an active ingredient together with oneor more pharmacologically acceptable pharmaceutical additives. In theaforementioned pharmaceutical compositions, a ratio of the activeingredient to the pharmaceutical additives is 1 weight % to 90 weight %.

The pharmaceutical compositions of the present invention may beadministered as pharmaceutical compositions for oral administration, forexample, granules, subtilized granules, powders, hard capsules, softcapsules, syrup, emulsion, suspension, or solution, or may beadministered as pharmaceutical compositions for parenteraladministration, for example, injections for intravenous administration,intramuscular administration, or subcutaneous administration, dripinfusions, suppositories, percutaneous absorbent, transmucosalabsorption preparations, nasal drops, ear drops, instillation, andinhalants. Preparations made as pharmaceutical compositions in a form ofpowder may be dissolved when necessary and used as injections or dripinfusions.

For preparation of pharmaceutical compositions, solid or liquidpharmaceutical additives may be used. Pharmaceutical additives mayeither be organic or inorganic. When an oral solid preparation isprepared, an excipient is added to the active ingredient, and furtherbinders, disintegrator, lubricant, colorant, corrigent are added, ifnecessary, to manufacture preparations in the forms of tablets, coatingtablets, granules, powders, capsules and the like by ordinaryprocedures. Examples of the excipient include lactose, sucrose,saccharose, glucose, corn starch, starch, talc, sorbit, crystalcellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide.Examples of the binder include, for example, polyvinyl alcohol,polyvinyl ether, ethyl cellulose, methyl cellulose, gum Arabic,tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, and pectin. Examples of thelubricant include, for example, magnesium stearate, talc, polyethyleneglycol, silica, and hydrogenated vegetable oil. As the coloring agent,any material can be used which are approved to be added to ordinarypharmaceuticals. As the corrigent, cocoa powder, menthol, aromatic acid,peppermint oil, d-borneol, cinnamon powder and the like can be used.These tables and granules may be applied with sugarcoating, gelatincoating, or an appropriate coating, if necessary. Preservatives,antioxidant and the like may be added, if required.

For liquid preparations for oral administration such as emulsions,syrups, suspensions, and solutions, ordinary used inactive diluents, forexample, water or vegetable oil may be used. For these preparations,besides inactive diluents, adjuvants such as wetting agents, suspendingaids, sweating agents, flavoring agents, coloring agents orpreservatives may be blended. After a liquid preparation ismanufactured, the preparation may be filled in capsules made of aabsorbable substance such as gelatin. Examples of solvents or suspendingagents used for the preparations of parenteral administration such asinjections or suppositories include, for example, water, propyleneglycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin.Examples of base materials used for preparation of suppositoriesinclude, for example, cacao butter, emulsified cacao butter, lauric fat,and witepsol. Methods for preparation of the aforementioned preparationsare not limited, and any method ordinarily used in the art may be used.

When the composition are prepared in the form of injections, carrierssuch as, for example, diluents including water, ethanol, macrogol,propylene glycol, citric acid, acetic acid, phosphoric acid, lacticacid, sodium lactate, sulfuric acid and sodium hydroxide, pH modifiersand buffer solutions including sodium citrate, sodium acetate and sodiumphosphate, stabilizers such as sodium pyrosulfite,ethylenediaminetetraacetic acid, thioglycolic acid and thiolactate maybe used. For the preparation, a sufficient amount of a salt, glucose,mannitol or glycerin may be blended in the preparation to manufacture anisotonic solution, and an ordinary solubilizer, a soothing agent, or atopical anesthetic may be used.

When the preparation in the form of an ointment such as a paste, acream, and a gel is manufactured, an ordinarily used base material, astabilizer, a wetting agent, and a preservative may be blended, ifnecessary, and may be prepared by mixing the components by a commonmethod. As the base material, for example, white petrolatum,polyethylene, paraffin, glycerin, cellulose derivatives, polyethyleneglycol, silicon, and bentonite may be used. As the preservative, paraoxymethyl benzoate, paraoxy ethyl benzoate, paraoxy propyl benzoate and thelike may be used. When the preparation in the form of a patch ismanufactured, the aforementioned ointment, cream gel, or paste and thelike may be applied by a common method to an ordinary support. As thesupport, fabric made of cotton, span rayon, and synthetic fibersor ornonwoven fabric, and a film or a foam sheet such as made of soft vinylchloride, polyethylene, and polyurethane and the like may be preferablyused.

A dose of the medicament of the present invention is not particularlylimited. For oral administration, a dose may generally be 0.01 to 5,000mg per day for an adult as the weight of the compound of the presentinvention. It is preferred to increase or decrease the above doseappropriately depending on the age, pathological conditions, andsymptoms of a patient. The above dose may be administered once a day or2 to 3 times a day as divided portions with appropriate intervals, orintermittent administration for every several days may be applied. Whenthe medicament is used as an injection, the dose may be 0.001 to 100 mgper day for an adult as the weight of the compound of the presentinvention.

EXAMPLES

The present invention will be explained more specifically with referenceto the following examples. However the scope of the present invention isnot limited to the following examples. The compound number in thefollowing examples correspond to those in the table shown above. And thecommercially available compounds, which were purchased and used for theexaminations, are contained in these examples. As for such compounds,the suppliers of the reagents and the catalog code numbers are shown.

Example 1 Preparation of the Compound of Compound No. 1

Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (it is abbreviated as WSC.HCl hereafter.; 192 mg, 1 mmol)was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol),3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol),4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10 mL),and the mixture was stirred at room temperature for 1 hour. The reactionmixture was poured into diluted hydrochloric acid and extracted withethyl acetate. After the organic layer was washed with water and brine,dried over anhydrous magnesium sulfate, the residue obtained byevaporation under reduced pressure was purified by chromatography onsilica gel(n-hexane:ethyl acetate=4:1) to give the title compound (244.8mg, 55.4%) as a white solid.

¹H-NMR(DMSO-d₆): δ 4.69(2H, d, J=5.7 Hz), 6.93(1H, d, J=8.7 Hz),7.56(1H, dd, J=8.7, 2.4 Hz), 8.02(1H, d, J=2.4 Hz), 8.06(3H, s),9.41(1H, t, J=5.7 Hz), 12.13(1H, s).

Example 2 Preparation of the Compound of Compound No. 2 (1)2-Acetoxy-N-(2-phenethyl)benzamide

O-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was dissolved in benzene(8 mL). Phenethylamine (0.12 g, 1.00 mmol) and pyridine (0.3 mL) wereadded, and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was poured into diluted hydrochloric acid and extractedwith ethyl acetate. After the organic layer was washed with water andbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation under reduced pressure was purified by chromatography onsilica gel(n-hexane:ethyl acetate=2:1→1:1) to give the title compound(155.5 mg, 54.9%) as a white crystal.

¹H-NMR(CDCl₃): δ 2.09(3H, s), 2.92(2H, t, J=6.8 Hz), 3.71(2H, q, J=6.8Hz), 6.32(1H, brs),7.07(1H, dd, J=8.4, 1.2 Hz), 7.23-7.35(6H, m),7.44(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.73(1H, dd, J=7.6, 1.6 Hz).

When the preparation method described in Example 2(1) is referred in thefollowing examples, organic bases such as pyridine, triethylamine or thelike were used as the base. As the reaction solvent, solvents such asdichloromethane, tetrahydrofuran, benzene or the like were used alone oras a mixture.

(2) 2-Hydroxy-N-(2-phenethyl)benzamide

Methanol (5 mL) and 2N sodium hydroxide (0.1 mL) were added to2-acetoxy-N-(2-phenethyl)benzamide (155.5 mg), and the mixture wasstirred at room temperature for 30 minutes. The reaction mixture waspoured into diluted hydrochloric acid and extracted with ethyl acetate.After the organic layer was washed with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was crystallized (dichloromethane/hexane) to give thetitle compound (106.9 mg, 80.7%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.86(2H, t, J=7.6 Hz), 3.52(1H, q, J=7.6Hz),6.84-6.88(2H, m), 7.18-7.31(5H, m), 7.37(1H, ddd, J=8.4, 7.2, 1.6Hz), 7.80(1H, dd, J=8.4, 1.6 Hz), 8.84(1H, s), 12.51(1H, s).

When the method described in Example 2(2) is referred in the followingexamples, inorganic bases such as sodium hydroxide, potassium carbonateor the like were used as the base. As the reaction solvent, solventssuch as water, methanol, ethanol, tetrahydrofuran or the like were usedalone or as a mixture.

(3) 5-Bromo-2-hydroxy-N-(2-phenethyl)benzamide (Compound No. 2)

Carbon tetrachloride (5 mL), iron powder (0.03 g) and bromine (25 μl,0.48 mmol) were added to 2-hydroxy-N-(2-phenethyl)benzamide (79.6 mg,0.33 mmol), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was poured into aqueous sodium hydrogen sulfite andextracted with ethyl acetate. After the organic layer was washed withbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation under reduced pressure was purified by chromatography onsilica gel(n-hexane:ethyl acetate=5:1) to give the title compound (62mg, 58.7%) as a white powder.

¹H-NMR(DMSO-d₆): δ 2.85(2H, t, J=7.6 Hz), 3.52(1H, q, J=7.6 Hz),6.87(1H,d, J=8.8 Hz), 7.18-7.31(5H, m), 7.52(1H, dd, J=8.8, 2.4 Hz), 8.01(1H, d,J=2.4 Hz), 8.90(1H, s), 12.51(1H, s).

Example 3 Preparation of the Compound of Compound No. 3

WSC.HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylicacid (109 mg, 0.5 mmol), 2-amino-5-(morpholino)carbonylindane (141 mg,0.5 mmol) and triethylamine (70 μL, 0.5 mmol) in dichloromethane (5 mL),and the mixture was stirred at 40° C. for 1.5 hours. After cooling, thereaction mixture was diluted with ethyl acetate, washed successivelywith 2N hydrochloric acid, water, and brine, dried over anhydrousmagnesium sulfate, concentrated, and the residue was purified by columnchromatography on silica gel(dichloromethane:methanol=19:1) to give thetitle compound (26 mg, 11.9%) as a white crystal.

¹H-NMR(CDCl₃): δ 2.66(1H, dd, J=16.2, 7.2 Hz), 2.82(1H, dd, J=16.2, 7.2Hz), 3.16-3.25(2H, m), 3.43-3.86(8H, m), 4.79-4.92(1H, m), 6.88(1H, d,J=8.7 Hz), 7.14-7.15(3H, m), 7.46(1H, dd, J=8.7, 2.4 Hz), 7.74(1H, d,J=7.8 Hz), 7.84(1H, d, J=2.4 Hz).

[2-Amino-5-(morpholino)carbonylindane: Refer to “Chemical andPharmaceutical Bulletin”, 2000, Vol. 48, p. 131.]

Example 4 The Compound of Compound No. 4

This compound is a commercially available compound.

-   Supplier: Apin Chemicals.-   Catalog code number: N 0100D.

Example 5 The Compound of Compound No. 5

This compound is a commercially available compound.

-   Supplier: Specs.-   Catalog code number: AI-233/31581024.

Example 6 The Compound of Compound No. 6

This compound is a commercially available compound.

-   Supplier: Maybridge.-   Catalog code number: RJC 00106.

Example 7 The Compound of Compound No. 7

This compound is a commercially available compound.

-   Supplier: Maybridge.-   Catalog code number: BTB 13230.

Example 8 The Compound of Compound No. 8

This compound is a commercially available compound.

-   Supplier: Maybridge.-   Catalog code number: BTB 114482.

Example 9 Preparation of the Compound of Compound No. 9

5-Chlorosalicylaldehyde (313 mg, 2 mmol) and4-chlorobenzyltriphenylphosphonium chloride (847 mg, 2 mmol) weredissolved in N,N-dimethylfomamide (20 mL). Potassium carbonate (1.382 g,10 mmol) dissolved in water (10 mL) was added, and the mixture wasrefluxed for 5 hours. After cooling, the reaction mixture was pouredinto 2N hydrochloric acid and extracted with ethyl acetate. After theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate, the residue obtained by evaporation under reducedpressure was purified by chromatography on silica gel(n-hexane:ethylacetate=3:1) to give the title compound (44.6 mg, 8.4%) as a light graysolid.

¹H-NMR(CDCl₃): δ 5.04(1H, s), 6.74(1H, d, J=9.0 Hz), 7.05(1H, d, J=16.5Hz), 7.10(1H, dd, J=8.4, 2.4 Hz), 7.26(1H, d, J=16.5 Hz), 7.33(2H, d,J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 7.49(1H, d, J=2.4 Hz).

Example 10 Preparation of the Compound of Compound No. 10 (1)5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide

5-Bromo-2-methoxybenzenesulfonyl chloride (857 mg, 3 mmol) was dissolvedin dichloromethane (6 mL). A solution of 3,5-dichloroaniline (510 mg,3.15 mmol) and pyridine (261 mg, 3.3 mmol) in dichloromethane (2 mL) wasadded dropwise under ice cooling and argon atmosphere, and the mixturewas stirred at room temperature for 6 hours. After the reaction mixturewas diluted with dichloromethane, washed successively with 2Nhydrochloric acid, water, and brine, dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure. The obtainedresidue was crystallized from n-hexane-ethyl acetate to give5-bromo-2-methoxy-N-(3,5-dichloro)benzenesulfonamide (900 mg, 73.0%) asa white crystal.

¹H-NMR(DMSO-d₆): δ 4.03(3H, s), 6.92(1H, d, J=9.0 Hz), 7.01(2H, d, J=1.8Hz), 7.07-7.08(1H, m), 7.24(1H, brs), 7.63(1H, dd, J=8.7, 2.4 Hz),7.99(1H, d, J=2.4 Hz).

(2) 5-Bromo-N-(3,5-dichlorophenyl)-2-hydroxybenzenesulfonamide (CompoundNo. 10)

A mixture of the white crystal of5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide (206 mg, 0.5mmol), lithium iodide (134 mg, 1 mmol) and 2,4,6-collidine (5 mL) wasrefluxed for 30 minutes under argon atmosphere. After cooling to roomtemperature, the reaction mixture was poured into 2N hydrochloric acidand extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and brine, dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure. The obtainedresidue was crystallized from n-hexane-ethyl acetate to give the titlecompound (90 mg, 45.3%) as a white crystal.

mp 158-159° C.

¹H-NMR(DMSO-d₆): δ 6.92(1H, d, J=8.7 Hz), 7.11(2H, d, J=2.1 Hz),7.21-7.22(1H, m), 7.62(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, d, J=2.4 Hz),10.70(1H, br), 11.37(1H, br).

Example 11 Preparation of the Compound of Compound No. 11

2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwiseunder ice cooling and argon atmosphere, and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure. The obtained residue was dissolved in ethanol (5 mL). 2NSodium hydroxide (0.1 mL, 0.2 mmol) was added dropwise, and the mixturewas stirred at room temperature for 30 minutes. The reaction mixture waspoured into 2N hydrochloric acid and extracted with ethyl acetate. Afterthe ethyl acetate layer was washed successively with water and brine,dried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure. The obtained residue was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=4:1) to give thetitle compound (288 mg, 73.6%) as a light pink crystal.

mp 183° C. (dec.).

¹H-NMR(DMSO-d₆): δ 6.83(1H, td, J=8.0, 1.2 Hz), 6.93(1H, dd, J=8.0, 1.2Hz), 7.08(1H, td, J=8.0, 1.6 Hz), 7.50(1H, d, J=8.0 Hz), 8.35(2H, s),9.61(1H, s), 10.15(1H, s).

Example 12 Preparation of the Compound of Compound No. 12

2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine (243 mg, 2.4mmol) were dissolved in dichloromethane (8 mL). A solution of3,5-dichlorobenzoyl chloride (419 mg, 2 mmol) in dichloromethane (2 mL)was added dropwise under ice cooling and argon atmosphere, and themixture was stirred at room temperature for 15 hours. After the reactionmixture was diluted with ethyl acetate, washed successively with waterand brine, dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=3:1) to givea light brown solid. The solid was suspended and washed withn-hexane-ethyl acetate under heating at reflux to give the titlecompound (205 mg, 32.4%) as a white crystal.

mp 251-252° C.

¹H-NMR(DMSO-d₆): δ 6.93(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7, 2.7 Hz),7.67(2H, d, J=2.7 Hz), 7.86-7.87(1H, m), 7.97(1H, d, J=1.8 Hz), 9.85(1H,s), 10.03(1H, s).

Example 13 Preparation of the Compound of Compound No. 13

2-Amino-4-chlorophenol (287 mg, 2 mmol) and 3,5-dichlorobenzenesulfonylchloride (540 mg, 2.2 mmol) were dissolved in dichloromethane (4 mL).Pyridine (1mL) was added dropwise under ice cooling and argonatmosphere, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was poured into 2N hydrochloric acid and extractedwith ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure. The obtainedresidue was purified by column chromatography on silicagel(n-hexane:ethyl acetate=3:1→1:1) to give a reddish brown solid. Thesolid was crystallized from n-hexane-ethyl acetate to give the titlecompound (445 mg, 63.1%) as a slight dark brown crystal.

mp 190-191° C.

¹H-NMR(DMSO-d₆): δ 6.68(1H, d, J=9.0 Hz), 7.08(1H, dd, J=8.7, 2.7 Hz),7.17(1H, d, J=2.4 Hz), 7.70(2H, d, J=1.8 Hz), 7.95-7.96(1H, m),10.00(1H, s), 10.06(1H, s).

Example 14 Preparation of the Compound of Compound No. 14 (1)4-Bromo-2-[(3,5-diphenylimino)methyl]phenyl

A mixture of 5-bromosalicylaldehyde (1.01 g, 5 mmol),3,5-dichloroaniline (810 mg, 5 mmol) and ethanol (25 mL) was refluxedfor 1 hour under argon atmosphere. After the reaction mixture was cooledto room temperature, the separated crystal was filtered to give thetitle compound (1.52 g, 88.2%) as an orange crystal.

mp 161-163° C.

¹H-NMR(CDCl₃): δ 6.94(1H, d, J=9.0 Hz), 7.16(2H, d, J=1.8 Hz),7.30-7.31(1H, m), 7.47-7.53(2H, m), 8.51(1H, s).

(2) N-[(5-Bromo-2-hydroxyphenyl)methyl]-3,5-dichloroaniline (CompoundNo. 14)

4-Bromo-2-[(3,5-diphenylimino)methyl]phenol (1.04 g, 3 mmol) wasdissolved in tetrahydrofuran (12 mL) and ethanol (6 mL). Sodiumborohydride (113 mg, 3 mmol) was added under ice cooling and argonatmosphere, and the mixture was stirred at room temperature for 12hours. Acetone (10 mL) was added to the reaction mixture. Water wasadded to the residue obtained by concentration under reduced pressure,and it was extracted with dichloromethane. After the dichloromethanelayer was washed successively with water and brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure.The obtained residue was purified by column chromatography on silicagel(n-hexane:ethyl acetate=4:1) to give a light yellow viscous material.This was crystallized by n-hexane to give the title compound (971 mg,93.3%) as a white crystal.

mp 125-126° C.

¹H-NMR(CDCl₃): δ 4.31(2H, s), 6.64(2H, d, J=1.8 Hz), 6.74-6.77(1H, m),6.84-6.85(1H, m), 7.30-7.34(2H, m).

Example 15 The Compound of Compound No. 15

This compound is a commercially available compound.

-   Supplier: Sigma-Aldrich.-   Catalog code number: S3203-5.

Example 16 Preparation of the Compound of Compound No. 16

A mixture of 5-chlorosalicylic acid (173 mg, 1 mmol),3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol), phosphorustrichloride (44 μl, 0.5 mmol) and monochlorobenzene (5 mL) was refluxedfor 3 hours under argon atmosphere. After the reaction mixture wascooled to room temperature, n-hexane (50 mL) was added, and theseparated crude crystal was filtered and dissolved in ethyl acetate (50mL). After the ethyl acetate solution was washed successively with waterand brine, dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=2:1) to givethe title compound (75 mg, 18.9%) as a white crystal.

¹H-NMR(CDCl₃): δ 3.57(3H, s), 6.59(1H, d, J=2.4 Hz), 6.94(1H, d, J=9.0Hz), 7.21(1H, dd, J=9.0, 2.7 Hz), 7.58(2H, s), 7.80(1H, s), 10.00(1H,brs).

When the method described in Example 16 is referred in the followingexamples, phosphorus trichloride was used as the acid halogenatingagent. As the reaction solvent, solvents such as monochlorobenzene,toluene or the like were used.

Example 17 Preparation of the Compound of Compound No. 17

Using 5-bromosalicylic acid and7-trifluoromethyl-1,2,3,4-tetrahydroquinoline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 42.0%.

¹H-NMR(CDCl₃): δ 2.08(2H, m), 2.92(2H, t, J=6.6 Hz), 3.95(2H, t, J=6.6Hz), 6.91-6.94(2H, m), 7.14(1H, s), 7.32-7.35(2H, m), 7.40(1H, dd,J=8.7, 2.4 Hz), 10.06(1H, s).

Example 18 Preparation of the Compound of Compound No. 18

Using 2-hydroxynaphthalene-1-carboxylic acid and 3,5-dichloroaniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 51.2%.

mp 246-248° C.

¹H-NMR(DMSO-d₆): δ 7.26(1H, d, J=9.3 Hz), 7.31-7.37(2H, m),7.44-7.50(1H, m), 7.65-7.68(1H, m), 7.85-7.90(4H, m), 10.23(1H, s),10.74(1H, s).

Example 19 Preparation of the Compound of Compound No. 19

Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 44.3%.

mp 254-255° C.

¹H-NMR(DMSO-d₆): δ 7.34-7.39(3H, m), 7.49-7.54(1H, m), 7.76-7.79(1H, m),7.89(2H, d, J=1.8 Hz), 7.92(1H, m), 8.39(1H, s), 10.75(1H, s), 11.01(1H,s).

Example 20 The Compound of Compound No. 20

This compound is a commercially available compound.

-   Supplier: Sigma-Aldrich.-   Catalog code number: S01361-8.

Example 21 Preparation of the Compound of Compound No. 21

Using 1-hydroxynaphthalene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 65.5%.

¹H-NMR(DMSO-d₆): δ 7.51(1H, d, J=9.0 Hz), 7.60(1H, td, J=7.8, 0.9 Hz),7.70(1H, td, J=7.8, 0.9 Hz), 7.89(1H, s), 7.93(1H, d, J=8.4 Hz),8.09(1H, d, J=9.0 Hz), 8.33(1H, d, J=8.7 Hz), 8.51(2H, s), 10.92(1H, s),13.36(1H, s).

Example 22 The Compound of Compound No. 22

This compound is a commercially available compound.

-   Supplier: Sigma-Aldrich.-   Catalog code number: S58026-0.

Example 23 The Compound of Compound No. 23

This compound is a commercially available compound.

-   Supplier: Sigma-Aldrich.-   Catalog code number: S63263-5.

Example 24 Preparation of the Compound of Compound No. 24

5-Chloro-2-hydroxynicotinic acid (174 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (275 mg, 1.2 mmol) and pyridine (316 mg,4 mmol) were dissolved in tetrahydrofuran (20 mL) and dichloromethane(10 mL). Phosphorus oxychloride (0.112 ml, 1.2 mmol) was added, and themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into ethyl acetate (100 mL) and 0.2N hydrochloricacid (100 mL), filtered through celite after stirring for 30 minutes,and the water layer of the filtrate was extracted with ethyl acetate.After the combined ethyl acetate layer was washed successively withwater and brine, dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=2:1→1:1) to give alight yellow solid. This was suspended and washed with ethanol underheating at reflux to give the title compound (183 mg, 47.6%) as a whitecrystal.

mp>270° C.

¹H-NMR(DMSO-d₆): δ 7.83(1H, s), 8.15(1H, d, J=3.3 Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).

When the preparation method described in Example 24 is referred in thefollowing examples, phosphorus oxychloride was used as the acidhalogenating agent. Pyridine was used as the base. As the reactionsolvent, solvents such as dichloromethane, tetrahydrofuran or the likewere used alone or as a mixture.

Example 25 Preparation of the Compound of Compound No. 25

Using 5-chloro-2-hydroxynicotinic acid and2-chloro-5-(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 24 gave the title compound.

Yield: 42.9%.

¹H-NMR(DMSO-d₆): δ 7.52(1H, dd, J=8.4, 2.1 Hz), 7.81(1H, d, J=8.4 Hz),8.16(1H, s), 8.39(1H, d, J=2.7 Hz), 8.96(1H, d, J=2.1 Hz), 12.76(1H, s),13.23(1H, s).

Example 26 Preparation of the Compound of Compound No. 26

Using 5-chloro-2-hydroxynicotinic acid and3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the sameoperation as the Example 24 gave the title compound.

Yield: 59.1%.

¹H-NMR(DMSO-d₆): δ 1.29(18H, s), 7.18(1H, t, J=1.8 Hz), 7.52(2H.d, J=1.8Hz), 8.07(1H, d, J=2.4 Hz), 8.35(1H, d, J=3.3 Hz), 11.92(1H, s),13.10(1H, s).

Example 27 Preparation of the Compound of Compound No. 27

Using 3-hydroxypyridine-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 24 gave the title compound.

Yield: 45.0%.

¹H-NMR(CDCl₃): δ 7.40(1H, dd, J=8.4, 1.8 Hz), 7.46(1H, dd, J=8.4, 4.2Hz), 7.68(1H, s), 8.16(1H, dd, J=4.2, 1.2 Hz), 8.25(2H, s), 10.24(1H,s), 11.42(1H, s).

Example 28 Preparation of the Compound of Compound No. 28

Under argon atmosphere, 3,5-bis(trifluoromethyl)phenylisocyanate (255mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL). A solution of6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) andtriethylamine (0.3 mL) were added, and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was poured into dilutedhydrochloric acid and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) togive the title compound (172.2 mg, 40.7%) as a pink solid.

¹H-NMR(DMSO-d₆): δ 3.97(2H, s), 7.29(1H, dd, J=8.1, 2.1 Hz), 7.41(1H, d,J=8.1 Hz), 7.88(1H, s), 8.04(1H, d, J=2.1 Hz), 8.38(2H, s), 10.93(1H,s).

Example 29 Preparation of the Compound of Compound No. 29

Using 3-hydroxyquinoxaline-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 2.7%.

¹H-NMR(DMSO-d₆): δ 7.40-7.45(2H, m), 7.69(1H, td, J=8.4, 1.5 Hz),7.90-7.93(2H, m), 8.41(2H, s), 11.64(1H, s), 13.02(1H, s).

Example 30 The Compound of Compound No. 30

This compound is a commercially available compound.

-   Supplier: Sigma-Aldrich.-   Catalog code number: S83846-2.

Example 31 The Compound of Compound No. 31

This compound is a commercially available compound.

-   Supplier: Maybridge.-   Catalog code number: RDR 01818.

Example 32 Preparation of the Compound of Compound No. 32

Using 5-chlorosalicylic acid and 1-naphthylamine as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 65.0%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.7 Hz), 7.51-7.61(4H, m), 7.85(1H, d,J=8.4 Hz), 7.96(1H, d, J=7.5 Hz), 7.99-8.05(2H, m), 8.13(1H, d, J=2.7Hz), 10.88(1H, s), 12.31(1H, s).

Example 33 Preparation of the Compound of Compound No. 33

Using 5-chlorosalicylic acid and 4-methoxy-2-naphthylamine as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 84.3%.

¹H-NMR(DMSO-d₆): δ 3.99(3H, s), 7.05(1H, d, J=9.0 Hz), 7.30(1H, d, J=1.5Hz), 7.39-7.45(1H, m), 7.48-7.54(2H, m), 7.83(1H, d, J=7.8 Hz), 8.00(1H,s), 8.02(1H, d, J=2.4 Hz), 8.09(1H, d, J=7.8 Hz), 10.54(1H, s),11.88(1H, s).

Example 34 Preparation of the Compound of Compound No. 34 (1)2-Acetoxy-5-chlorobenzoic acid

Concentrated sulfuric acid (0.08 mL) was added slowly to a mixture of5-chlorosalicylic acid (13.35 g, 77 mmol) and acetic anhydride (20 mL).After the reaction mixture was solidified, it was poured into ice waterand extracted with ethyl acetate. The organic layer was washed withwater and brine, and dried over anhydrous sodium sulfate. The residueobtained by evaporation of the solvent under reduced pressure was washedwith n-hexane under suspension to give the title compound (15.44 g,93.0%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 2.25(3H, s), 7.27(1H, d, J=8.7 Hz), 7.72(1H, dd,J=8.7, 2.7 Hz), 7.89(1H, d, J=2.7 Hz), 13.47(1H, s).

(2) 2-Acetoxy-5-chloro-N-(1-methoxynaphthalen-3-yl)benzamide (CompoundNo. 34)

Using 2-acetoxy-5-chlorobenzoic acid and 4-methoxy-2-naphthylamine asthe raw materials, the same operation as the Example 24 gave the titlecompound.

Yield: 39.9%, red solid.

¹H-NMR(DMSO-d₆): δ 2.23(3H, s), 3.96(3H, s), 7.23(1H, d, J=1.2 Hz),7.34(1H, d, J=8.7 Hz), 7.40(1H, dt, J=8.1, 1.2 Hz), 7.50(1H, dt, J=8.1,1.5 Hz), 7.67(1H, dd, J=8.7, 2.7 Hz), 7.81(1H, d, J=8.7 Hz), 7.82(1H, d,J=3.0 Hz), 8.02(1H, s), 8.08(1H, d, J=8.7 Hz), 10.58(1H, s).

Example 35 Preparation of the Compound of Compound No. 35

Using 5-chlorosalicylic acid and2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethylester as the raw materials, the same operation as the Example 16 gavethe title compound.

Yield: 49.6%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=7.2 Hz), 1.74(4H, br), 2.63(2H, br),2.75(2H, br), 4.30(2H, q, J=7.2 Hz), 7.05(1H, d, J=9.0 Hz), 7.50(1H, dd,J=8.7, 3.0 Hz), 7.92(1H, d, J=3.0 Hz), 12.23(1H, s), 13.07(1H, s).

Example 36 Preparation of the Compound of Compound No. 36

Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 9.2%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.01(1H, s),7.35(1H, t, J=7.6Hz), 7.46(2H, t, J=7.6 Hz), 7.58(1H, dd, J=8.8, 2.8 Hz), 7.74-7.76(2H,m), 8.19(1H, s), 10.86(1H, s), 12.09(1H, s), 13.00(1H, brs).

Example 37 Preparation of the Compound of Compound No. 37 (1)2-Amino-4,5-diethyloxazole

Propioin (1.03 g, 8.87 mmol) was dissolved in ethanol (15 mL). Cyanamide(0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added,and the mixture was stirred at room temperature for 3.5 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.After the organic layer was washed with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was purified by chromatography on silicagel(dichloromethane:methanol=9:1) to give the title compound (369.2 mg,29.7%) as an yellow amorphous.

¹H-NMR(DMSO-d₆): δ 1.04(3H, t, J=7.5 Hz), 1.06(3H, t, J=7.5 Hz),2.20(2H, q, J=7.5 Hz), 2.43(2H, q, J=7.5 Hz), 6.15(2H, s).

(2) 2-Acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide

Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole asthe raw materials, the same operation as the Example 24 gave the titlecompound.

Yield: 22.0%.

¹H-NMR(CDCl₃): δ 1.22(3H, t, J=7.5 Hz), 1.23(3H, t, J=7.5 Hz), 2.38(3H,s), 2.48(2H, q, J=7.5 Hz), 2.57(2H, q, J=7.5 Hz), 6.96(1H, d, J=8.7 Hz),7.58(1H, dd, J=8.7, 2.7 Hz), 8.32(1H, s), 11.40(1H, br).

[2-Acetoxy-5-bromosalicylic acid: It was obtained, using5-bromosalicylic acid and acetic anhydride as the raw materials, by thesame operation as the Example 34(1) with reference to “Europian Journalof Medicinal Chemistry”, 1996, Vol. 31, p. 861-874.]

(3) 5-Bromo-N-(4,5-diethyloxazol-2-yl)-2-hydroxybenzamide (Compound No.37)

Using 2-acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide as the rawmaterial, the same operation as the Example 2(2) gave the titlecompound.

Yield: 70.2%.

¹H-NMR(CDCl₃) δ :1.25(3H, t, J=7.5 Hz), 1.26(3H, t, J=7.5 Hz), 2.52(2H,q, J=7.5 Hz), 2.60(2H, q, J=7.5 Hz), 6.84(1H, d, J=8.7 Hz), 7.43(1H, dd,J=8.7, 3.0 Hz), 8.17(1H, d, J=3.0 Hz), 11.35(1H, br), 12.83(1H, br).

Example 38 Preparation of the Compound of Compound No. 38

Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 32.6%.

mp 188-189° C.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.40-7.49(6H, m),7.53-7.56(2H, m), 7.59-7.63(3H, m), 8.01(1H, d, J=2.4 Hz), 11.80(2H,brs).

[2-Amino-4,5-diphenyloxazole: Refer to “Zhournal Organicheskoi Khimii:Russian Journal of Organic Chemistry”, (Russia), 1980, Vol. 16, p.2185.]

Example 39 Preparation of the Compound of Compound No. 39 (1)2-Amino-4,5-bis(furan-2-yl)oxazole

Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide(218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) wereadded, and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was poured into water and extracted with ethyl acetate.After the organic layer was washed with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was purified by chromatography on silicagel(hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg,31.1%) as a dark brown crystal.

¹H-NMR(DMSO-d₆): δ 6.59(1H, dd, J=3.3,2.1 Hz), 6.62(1H, dd, J=3.3, 2.1Hz), 6.73(1H, dd, J=3.3, 0.6 Hz), 6.80(1H, dd, J=3.3, 0.9 Hz), 7.05(2H,s), 7.75-7.76(2H, m).

(2) 5-Bromo-N-[4,5-bis(furan-2-yl)oxazol-2-yl]-2-hydroxybenzamide(Compound No. 39)

Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 12.9%.

¹H-NMR(DMSO-d₆): δ 6.65(1H, dd, J=3.6, 1.8 Hz), 6.68(1H, dd, J=3.6, 1.8Hz), 6.75(1H, d, J=8, 7 Hz), 6.92(1H, dd, J=3.6, 0.9 Hz), 6.93(1H, d,J=3.3 Hz), 7.37(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, dd, J=1.8, 0.9 Hz),7.84(1H, dd, J=1.8, 0.9 Hz), 7.92(1H, d, J=3.0 Hz), 14.88(2H, br).

Example 40 Preparation of the Compound of Compound No. 40 (1)2-Acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide

Using O-acetylsalicyloyl chloride and2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, thesame operation as the Example 2(1) gave the title compound.

Yield: 51.1%.

¹H-NMR(DMSO-d₆): δ 2.23(3H, s), 7.32(1H, dd, J=8.0, 1.2 Hz),7.45(1H, td,J=7.6, 1.2 Hz), 7.69(1H, td, J=8.0, 2.0 Hz), 7.87(1H, dd, J=8.0, 2.0Hz), 13.75(1H, brs).

(2) 2-Hydroxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide(Compound No. 40)

Using 2-acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide asthe raw material, the same operation as the Example 2(2) gave the titlecompound.

Yield: 92.9%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, td, J=8.0, 0.8 Hz),7.06(1H, d, J=8.4 Hz),7.51(1H, ddd, J=8.4, 7.6, 2.0 Hz), 7.92(1H, dd, J=8.0, 1.6 Hz),12.16(1H, br).

Example 41 Preparation of the Compound of Compound No. 41

Using 5-bromosalicylic acid and2-amino-5-trifluoromethyl-1,3,4-thiadiazole as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 80.2%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=9.0 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz),7.97(1H, d, J=2.4 Hz).

Example 42 Preparation of the Compound of Compound No. 42

Using 5-chlorosalicylic acid and 5-amino-2-chloropyridine as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 12.2%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 3.0 Hz),7.54(1H, d, J=8.4 Hz), 7.88(1H, d, J=2.7 Hz), 8.21(1H, dd, J=8.7, 2.7Hz), 8.74(1H, d, J=2.7 Hz), 10.62(1H, s), 11.57(1H, s).

Example 43 Preparation of the Compound of Compound No. 43

Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 2.2%, white solid.

¹H-NMR(DMSO-d₆): δ 3.86(3H, s), 6.85(1H, s), 7.01(1H, d, J=9.0 Hz),7.47(1H, dd, J=9.0, 3.0 Hz), 7.81(1H, d, J=3.0 Hz), 11.08(1H, s),11.65(1H, s).

Example 44 Preparation of the Compound of Compound No. 44

Using 2-acetoxy-5-chlorobenzoic acid and 5-aminoindole as the rawmaterials, the same operation as the Example 24 gave the title compound.

Yield: 13.3%.

¹H-NMR(DMSO-d₆): δ 2.20(3H, s), 6.41(1H, t, J=2.1 Hz), 7.27-7.36(4H, m),7.63(1H, dd, J=8.7, 2.7 Hz), 7.74(1H, d, J=2.7 Hz), 7.93(1H, s),10.21(1H, s), 11.04(1H, s).

Example 45 The Compound of Compound No. 45

This compound is a commercially available compound.

-   Supplier: Peakdale.-   Catalog code number: PFC-0448.

Example 46 Preparation of the Compound of Compound No. 46

Using 5-chlorosalicylic acid and 3-aminoquinoline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 4.3%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.51(1H, dd, J=9.0, 3.0 Hz),7.61(1H, dt, J=7.8, 1.2 Hz), 7.70(1H, dt, J=7.8, 1.5 Hz), 7.98(2H, d,J=3.0 Hz), 8.01(1H, s), 8.82(1H, d, J=2.4 Hz), 10.80(1H, s), 11.74(1H,s).

Example 47 Preparation of the Compound of Compound No. 47

Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 64.6%.

¹H-NMR(DMSO-d₆): δ 1.33(3H, t, J=7.0 Hz), 4.46(2H, q, J=7.0 Hz),7.04(1H, d, J=9.0 Hz), 7.21(1H, t, J=7.3 Hz), 7.45-7.52(2H, m),7.64-7.65(2H, m), 7.70(1H, d, J=8.4, 1.9 Hz), 8.11-8.15(2H, m), 8.49(1H,d, J=1.9 Hz), 10.55(1H, s), 12.22(1H, s).

Example 48 Preparation of the Compound of Compound No. 95

Using O-acetylsalicyloyl chloride and 3,5-bis(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 2(1) gave the titlecompound.

Yield: 84.2%.

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 7.19(1H, dd, J=8.0, 1.2 Hz), 7.39(1H,td, J=7.6, 1.2 Hz), 7.57(1H, ddd, J=8.0, 7.6, 1.6 Hz), 7.65(1H, s),7.83(1H, dd, J=8.0, 1.6 Hz), 8.11(2H, s), 8.31(1H, s).

Example 49 Preparation of the Compound of Compound No. 48

Using 2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (CompoundNo. 95) as the raw material, the same operation as the Example 2(2) gavethe title compound.

Yield: 45.1%.

¹H-NMR(DMSO-d₆): δ 6.96-7.02(2H, m), 7.45(1H, ddd, J=8.0, 7.2, 1.6 Hz),7.81(1H, s), 7.87(1H, dd, J=8.0, 1.6 Hz), 8.46(2H, s), 10.80(1H, s),11.26(1H, s).

Example 50 Preparation of the Compound of Compound No. 49

Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 58.7%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, ddd, J=9.0, 4.5, 1.2 Hz), 7.30-7.37(1H, m),7.66(1H, ddd, J=9.0, 3.3, 1.2 Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H,s), 11.21(1H, brs).

Example 51 Preparation of the Compound of Compound No. 50

Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 85.5%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz),7.85(1H, s), 7.87(1H, d, J=2.7 Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H,s).

Example 52 Preparation of the Compound of Compound No. 51

Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 88.5%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.8 Hz),7.83(1H, s), 7.98(1H, d, J=2.8 Hz), 8.43(2H, s), 10.82(1H, s), 11.37(1H,s).

This compound was obtained also by the following preparation method.

Iron powder (30 mg, 0.54 mmol) and bromine (0.02 mL, 0.39 mmol) wereadded to a solution of 2-acetoxy-N-[3,5-bis(trifluoromethyl)]benzamide(Compound No. 95; 100 mg, 0.25 mmol) in carbon tetrachloride (8 mL), andthe mixture was stirred at 50° C. for 4 hours. After the reactionmixture was cooled to room temperature, it was poured into aqueousNaHSO₄ and extracted with ethyl acetate. The ethyl acetate layer waswashed with water and brine, and dried over anhydrous sodium sulfate.The residue obtained by evaporation of the solvent under reducedpressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=4:1) to give the title compound (600 mg,54.9%) as a white solid.

Example 53 Preparation of the Compound of Compound No. 52

Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 62.2%.

¹H-NMR(DMSO-d₆): δ 6.86(1H, d, J=8.4 Hz), 7.74(1H, dd, J=8.7, 2.4 Hz),7.84(1H, s), 8.13(1H, d, J=2.1 Hz), 8.84(2H, s), 10.82(1H, s), 11.41(1H,s).

Example 54 Preparation of the Compound of Compound No. 53

Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 57.2%.

¹H-NMR(DMSO-d₆):d 7.18(1H, d, J=9.0 Hz), 7.86(1H, s), 8.31(1H, dd,J=9.0, 3.0 Hz), 8.45(2H, s), 8.70(1H, d, J=3.0 Hz), 11.12(1H, s).

Example 55 Preparation of the Compound of Compound No. 54 (1)2-Benzyloxy-5-formylbenzoic acid benzyl ester

A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol), benzyl bromide(15.39 g, 90 mmol), potassium carbonate (16.59 g, 120 mmol), and methylethyl ketone (350 mL) was refluxed for 8 hours. After cooling, thesolvent was evaporated under reduced pressure. 2N Hydrochloric acid wasadded to the residue, and the mixture was extracted with ethyl acetate.The layer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=3:1), suspended and washed with isopropylether under heating at reflux to give the title compound (5.98 g, 57.5%)as a white solid.

¹H-NMR(CDCl₃):d 5.27(2H, s), 5.37(2H, s), 7.15(1H, d, J=9.0 Hz),7.26-7.46(10H, m), 7.99(1H, dd, J=9.0, 2.4 Hz), 8.36(1H, d, J=2.4 Hz),9.91(1H, s).

(2) 2-Benzyloxy-5-cyanobenzoic acid benzyl ester

A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester (693 mg, 2mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol), andN-methylpyrrolidone (3 mL) was stirred at 115 □ for 4 hours. After thereaction mixture was cooled, 2N hydrochloric acid (5 mL) and water (30mL) were added and the mixture was extracted with ethyl acetate. Theorganic layer was washed with 2N aqueous sodium hydroxide, water, andbrine, and dried over anhydrous magnesium sulfate. The residue obtainedby evaporation of the solvent under reduced pressure was suspended andwashed with isopropyl ether under heating at reflux to give the titlecompound (527 mg, 76.7%) as a white solid.

¹H-NMR(CDCl₃):d 5.23(2H, s), 5.35(2H, s), 7.08(1H, d, J=8.7 Hz), 7.33-7,43(10H, m), 7.70(1H, dd, J=8.7, 2.4 Hz), 8.13(1H, d, J=2.4 Hz).

(3) 5-Cyanosalicylic acid

Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5%palladium on carbon (45 mg), and the mixture was hydrogenated at roomtemperature for 2 hours. After the insoluble matter was filtered off,the solvent was evaporated under reduced pressure to give the titlecompound (212 mg, 100.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.7 Hz), 7.82(1H, dd, J=8.7, 2.4 Hz),8.12(1H, d, J=2.1 Hz).

(4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-cyano-2-hydroxybenzamide(Compound No. 54)

Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 16.6%.

¹H-NMR(DMSO-d₆): δ 7.15(1H, d, J=8.7 Hz), 7.85(1H, s), 7.86(1H, dd,J=8.7, 2.1 Hz), 8.22(1H, d, J=2.4 Hz), 8.43(2H, s), 10.93(1H, s),12.00(1H, brs).

Example 56 Preparation of the Compound of Compound No. 55

Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 54.9%.

¹H-NMR(DMSO-d₆): δ 6.92(1H, d, J=8.7 Hz), 7.28(1H, dd, J=8.7, 1.8 Hz),7.71(1H, d, J=1.8 Hz), 7.82(1H, s), 8.47(2H, s), 10.80(1H, s), 11.14(1H,s).

Example 57 Preparation of the Compound of Compound No. 56 (1)5-[(1,1-Dimethyl)ethyl]salicylic acid

Sulfamic acid (1.76 g, 18.1 mmol) and sodium dihydrogenphosphate (7.33g, 47 mmol) were added to a solution of5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol) in1,4-dioxane (100 mL) and water (40 mL). A solution of sodium chlorite(1.76 g, 15.5 mmol) in water (10 mL) was added to the mixture under icecooling, and it was stirred for 1 hour. Then, sodium sulfite (1.80 g,14.3 mmol) was added to the mixture, and it was stirred for 30 minutes.Concentrated hydrochloric acid was added to the reaction mixture, and pHwas adjusted to 1. The residue obtained by evaporation of 1,4-dioxaneunder reduced pressure was extracted with ethyl acetate. The organiclayer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The residue obtained by evaporation of the solventunder reduced pressure was washed with n-hexane under suspension to givethe title compound (1.81 g, 77.4%) as a white powder.

¹H-NMR(DMSO-d₆): δ 1.26(9H, s), 6.90(1H, d, J=9.0 Hz), 7.58(1H, dd,J=8.7, 2.4 Hz), 7.75(1H, d, J=2.4 Hz), 11.07(1H, brs).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-5-[(1,1-dimethyl)ethyl]-2-hydroxybenzamide(Compound No. 56)

Using 5-[(1,1-dimethyl)ethyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 53.8%.

¹H-NMR(DMSO-d₆): δ 1.30(9H, s), 6.96(1H, d, J=8.7 Hz), 7.50(1H, dd,J=8.7, 2.4 Hz), 7.82(1H, d, J=2.4 Hz), 7.83(1H, s), 8.46(2H, s),10.80(1H, s)11.12(1H, s).

Example 58 Preparation of the Compound of Compound No. 78 (1)5-Acetyl-2-benzyloxybenzoic acid methyl ester

A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol),benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140mmol) and methyl ethyl ketone (350 mL) was refluxed for 8 hours. Aftercooling, the solvent was evaporated under reduced pressure. 2NHydrochloric acid was added to the residue, and it was extracted withethyl acetate. After the ethyl acetate layer was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated, theresidue was recrystallized from isopropyl ether to give the titlecompound (14.20 g, 71.4%) as a white solid.

¹H-NMR(CDCl₃): δ 2.58(3H, s), 3.93(3H, s), 5.27(2H, s), 7.07(1H, d,J=8.7 Hz), 7.26-7.43(3H, m), 7.47-7.50(2H, m), 8.07(1H, dd, J=8.7, 2.4Hz), 8.44(1H, d, J=2.4 Hz).

(2) 5-Acetyl-2-benzyloxybenzoic acid

5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20 mmol) wasdissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (20mL). 2N Sodium hydroxide (11 mL) was added dropwise, and the mixture wasstirred for 8 hours. The solvent was evaporated under reduced pressure.2N Hydrochloric acid was added to the residue, and it was extracted withdichloromethane. After the dichloromethane layer was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated, theresidue was washed with isopropyl ether to give the title compound (4.92g, 91.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.55(3H, s), 5.32(2H, s), 7.30-7.43(4H, m),7.49-7.52(2H, m), 8.09(1H, dd, J=9.0, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).

(3) 5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide

Using 5-acetyl-2-benzyloxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 24 gave the title compound.

Yield: 63.1%.

¹H-NMR(DMSO-d₆): δ 2.57(3H, s), 7.11(1H, d, J=8.7 Hz), 7.86(1H, s),8.05(1H, dd, J=8.4, 2.1 Hz), 8.44(1H, d, J=2.1 Hz), 8.47(2H, s),10.96(1H, s), 11.97(1H, brs).

(4) 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 78)

Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602mg, 1.25 mmol) and 5% palladium on carbon (60 mg), and the mixture washydrogenated at room temperature for 30 minutes. After the insolublematter was filtered off, the solvent was evaporated under reducedpressure and the residue was recrystallized from n-hexane-ethyl acetateto give the title compound (230 mg, 47.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.59(3H, s), 5.35(2H, s), 7.32-7.36(3H, m), 7.43(1H,d, J=8.7 Hz), 7.52-7.55(2H, m), 7.82(1H, s), 8.16(1H, dd, J=8.7, 2.4Hz), 8.25(1H, d, J=2.4 Hz), 8.31(2H, s), 10.89(1H, s).

Example 59 Preparation of the Compound of Compound No. 57

5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 78; 50.5 mg, 0.13 mmol) was suspended in ethanol (2 mL). Sodiumborohydride (23.6 mg, 0.62 mmol) was added, and the mixture was stirredat room temperature for 12 hours. The reaction mixture was poured intodiluted hydrochloric acid and extracted with ethyl acetate. After theorganic layer was washed with water and brine, dried over anhydroussodium sulfate, the residue obtained by evaporation under reducedpressure was washed with isopropyl ether/n-hexane under suspension togive the title compound (39.7 mg, 78.3%) as a white powder.

¹H-NMR(DMSO-d₆): δ 1.34(3H, d, J=6.3 Hz), 4.71(1H, q, J=6.3 Hz),5.18(1H, brs), 6.97(1H, d, J=8.4 Hz), 7.44(1H, dd, J=8.4, 2.1 Hz),7.84(1H, s), 7.86(1H, d, J=2.1 Hz), 8.48(2H, s), 10.85(1H, s), 11.32(1H,s).

Example 60 Preparation of the Compound of Compound No. 58

5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 78; 100.0 mg, 0.26 mmol) was dissolved in ethanol (3 mL). Pyridine(45 μl, 0.56 mmol) and O-methylhydroxylamine hydrochloride (25.8 mg,0.31 mmol) were added, and the mixture was refluxed for 1 hour. Aftercooling, the reaction mixture was poured into diluted hydrochloric acidand extracted with ethyl acetate. After the organic layer was washedwith water and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation under reduced pressure was purified bychromatography on silica gel(hexane:ethyl acetate=4:1) to give the titlecompound (102.1 mg, 95.3%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 2.19(3H, s), 3.91(3H, s), 7.05(1H, d, J=8.7Hz),7.77(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.09(1H, d, J=2.4 Hz),8.47(2H, s), 10.87(1H, s), 11.48(1H, s).

Example 61 Preparation of the Compound of Compound No. 59

Using 5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 78) and O-benzylhydroxylamine hydrochloride as the rawmaterials, the same operation as the Example 60 gave the title compound.

Yield: 79.9%.

¹H-NMR(DMSO-d₆): δ 2.24(3H, s), 5.20(2H, s), 7.04(1H, d, J=8.7 Hz),7.29-7.47(5H, m), 7.76(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 8.07(1H, d,J=2.1 Hz), 8.46(2H, s), 10.87(1H, s), 11.47(1H, s).

Example 62 Preparation of the Compound of Compound No. 60 (1)5-(2,2-Dicyanoethen-1-yl)-2-hydroxybenzoic acid

Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling withice bath, benzylamine (0.1 mL) was added and the mixture was stirred atroom temperature for 2 hours. The separated yellow crystal was filteredand recrystallized (ethanol) to give the title compound (139.9 mg,32.7%) as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.7 Hz), 8.09(1H, dd, J=8.7, 2.4 Hz),8.41(1H, s), 8.50(1H, d, J=2.4 Hz).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzamide(Compound No. 60)

Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 9.1%.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=9.0 Hz), 7.83(1H, s), 8.04(1H, dd,J=9.0, 2.4 Hz), 8.36(1H, s), 8.38(1H, d, J=2.4 Hz), 8.43(2H, s),11.43(1H, s).

Example 63 Preparation of the Compound of Compound No. 62 (1)5-[(2-Cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid

Triethylamine (0.2 ml) was added to a mixture of 5-formylsalicylic acid(332 mg, 2 mmol). Cyanoacetic acid methyl ester (198 mg, 2 mmol) andacetic acid (6 mL), and the mixture was refluxed for 5 hours. Aftercooling, the reaction mixture was poured into water, and the separatedcrystal was filtered and recrystallized (n-hexane) to give the titlecompound (327.7 mg, 66.3%) as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.15(1H, d, J=8.7 Hz), 8.20(1H, dd,J=8.7, 2.4 Hz), 8.37(1H, s), 8.66(1H, d, J=2.4 Hz).

(2)3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl-4-hydroxyphenyl)-2-cyanoacrylicacid methyl ester (Compound No. 62)

Using 5-[(2-cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acidand 3,5-bis(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 66.3%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.19(1H, d, J=9.0 Hz), 7.85(1H, s),8.20(1H, dd, J=8.7, 2.1 Hz), 8.33(1H, s), 8.45(2H, s), 8.50(1H, d, J=2.1Hz), 11.00(1H, s), 11.03(1H, s).

Example 64 Preparation of the Compound of Compound No. 61

3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cyanoacrylicacid methyl ester (Compound No. 62; 50 mg, 0.11 mmol) was dissolved inethanol (5 mL). 2N Sodium hydroxide (0.11 ml, 0.22 mmol) was added, andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was poured into diluted hydrochloric acid and extracted withethyl acetate. After the organic layer was washed with brine, dried overanhydrous magnesium sulfate, the residue obtained by evaporation underreduced pressure was recrystallized (ethyl acetate) to give the titlecompound (13.5 mg, 30.4%) as a light yellow solid.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.4 Hz), 7.84(1H, s), 7.94(1H, dd,J=8.4, 2.1 Hz), 8.38(1H, d, J=2.1 Hz), 8.45(2H, s), 9.87(1H, s),11.41(1H, s).

Example 65 Preparation of the Compound of Compound No. 63

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 52; 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate(4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine (12.2 mg, 0.04 mmol),diisopropylamine (388 mg, 3 mmol) and N,N-dimethylformamide (2 mL) wasrefluxed for 8 hours. After cooling, water was added to the reactionmixture, and it was extracted with ethyl acetate. After the ethylacetate layer was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated, the residue was purified by columnchromatography on silica gel(n-hexane:isopropyl ether=2:1→1:1) to givethe title compound (173 mg, 38.3%) as a pale yellow solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.4 Hz), 7.20-7.29(3H, m), 7.38(2H, t,J=7.5 Hz), 7.59(2H, d, J=7.5 Hz), 7.72(1H, dd, J=8.4, 2.1 Hz), 7.86(1H,s), 8.07(1H, d, J=2.1 Hz), 8.49(2H, s), 10.89(1H, s), 11.33(1H, brs).

Example 66 Preparation of the Compound of Compound No. 66

N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 52; 950 mg, 2 mmol) and trimethylsilylacetylene (246 mg, 2.5 mmol)were dissolved in triethylamine (2 mL) and N,N-dimethylformamide (4 mL).Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprousiodide (4 mg, 0.02 mmol) were added under argon atmosphere, and themixture was stirred at 40° C. for 2 hours. After cooling to roomtemperature, the reaction mixture was poured into ethyl acetate (100 mL)and 1N citric acid (100 mL), stirred, and filtered through celite. Afterthe ethyl acetate layer was washed successively with water and brine,dried over anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure. The obtained residue was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=19:1) to give alight orange solid. This was crystallized by n-hexane to give the titlecompound (286 mg, 32.1%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 0.23(9H, s), 7.00(1H, d, J=8.7 Hz), 7.54(1H, dd,J=8.7, 2.4 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s),10.86(1H, s), 11.69(1H, s).

Example 67 Preparation of the Compound of Compound No. 64

N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)ethynyl]-benzamide(Compound No. 66; 233 mg, 0.5 mmol) was dissolved in methanol (1 mL). 2NSodium hydroxide (1 mL) was added, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure. The obtained residue was crystallized from ethanol-water togive the title compound (67 mg, 35.9%) as a light gray crystal.

¹H-NMR(DMSO-d₆): δ 4.11(1H, s), 7.02(1H, d, J=8.4 Hz), 7.55(1H, dd,J=8.4, 2.1 Hz), 7.85(1H, s), 7.98(1H, d, J=2.1 Hz), 8.46(2H, s),8.46(2H, s), 10.86(1H, s), 11.62(1H, s).

Example 68 Preparation of the Compound of Compound No. 65

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 52) and phenylacetylene as the raw materials, the sameoperation as the Example 66 gave the title compound.

Yield: 40.8%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.4 Hz), 7.42-7.46(3H, m),7.53-7.57(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.86(1H, s), 8.06(1H, d,J=2.1 Hz), 8.48(2H, s), 10.94(1H, s), 11.64(1H, brs).

Example 69 Preparation of the Compound of Compound No. 67

N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 52; 200 mg, 0.42 mmol) was dissolved in 1,2-dimethoxyethane (3 mL),Tetrakis(triphenylphosphine)palladium (16 mg, 0.0014 mmol) was addedunder argon atmosphere, and the mixture was stirred at room temperaturefor 5 minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1Msodium carbonate (1.3 mL) were added and the mixture was refluxed for 2hours. After cooling to room temperature, the reaction mixture waspoured into diluted hydrochloric acid and extracted with ethyl acetate.After the ethyl acetate layer was washed successively with water andbrine, dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure. The obtained residue was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=6:1→3:1) to give thetitle compound (109 mg, 61.1%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.12(1H, d, J=8.7 Hz), 7.33-7.38(1H, m), 7.48(2H, t,J=7.5 Hz), 7.67-7.70(2H, m), 7.79(1H, dd, J=8.4, 2.4 Hz), 7.87(1H, s),8.17(1H, d, J=2.4 Hz), 8.49(2H, s), 10.92(1H, s), 11.41(1H, s).

Example 70 Preparation of the Compound of Compound No. 68

UsingN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(phenylethynyl)benzamide(Compound No. 65) as the raw material, the same operation as the Example58(4) gave the title compound.

Yield: 86.2%.

¹H-NMR(DMSO-d₆): δ 2.88(4H, s), 6.93(1H, d, J=8.1 Hz), 7.15-7.34(6H, m),7.76(1H, d, J=2.4 Hz), 7.84(1H, s), 8.47(2H, s), 10.79(1H, s), 11.15(1H,s).

Example 71 Preparation of the Compound of Compound No. 69

Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 44.7%.

¹H-NMR(CDCl₃): δ 7.17(1H, d, J=9.0 Hz) 7.72-7.75(2H, m), 7.86(1H, s),8.17(2H, s), 8.35(1H, s) 11.88(1H, s).

[2-Hydroxy-5-(trifluoromethyl)benzoic acid: Refer to “Chemical andPharmaceutical Bulletin”, 1996, Vol. 44, p. 734.]

Example 72 Preparation of the Compound of Compound No. 70

Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

¹H-NMR(CDCl₃): δ 7.19(1H, d, J=9.0 Hz) 7.70(1H, dd, J=8.7, 2.1 Hz),7.81(1H, d, J=2.1 Hz), 8.17(2H, s), 8.37(1H, s), 11.92(1H, s).

[2-Hydroxy-5-(pentafluoromethyl)benzoic acid: Refer to “Chemical andPharmaceutical Bulletin”, 1996, Vol. 44, p. 734.]

Example 73 Preparation of the Compound of Compound No. 71

Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 57.8%.

¹H-NMR(DMSO-d₆): δ 6.27(2H, dd, J=2.4, 1.8 Hz), 7.10(1H, d, J=9.0 Hz),7.29(2H, dd, J=2.4, 1.8 Hz), 7.66(1H, dd, J=9.0, 2.7 Hz), 7.86(1H, s),7.98(1H, d, J=2.4 Hz), 8.47(2H, s), 10.89(1H, s), 11.24(1H, s).

Example 74 Preparation of the Compound of Compound No. 72

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 52) and 2-thiopheneboronic acid as the raw materials, thesame operation as the Example 69 gave the title compound.

Yield: 44.4%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.4 Hz), 7.14(1H, dd, J=5.4, 3.6 Hz),7.45(1H, dd, J=3.6, 1.2 Hz), 7.51(1H, dd, J=5.1, 0.9 Hz), 7.75(1H, dd,J=8.4, 2.4 Hz), 7.59(1H, s), 8.08(1H, d, J=2.4 Hz), 8.48(2H, s),10.91(1H, s), 11.38(1H, s).

Example 75 Preparation of the Compound of Compound No. 73

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide(Compound No. 52) and 3-thiopheneboronic acid as the raw materials, thesame operation as the Example 69 gave the title compound.

Yield: 38.7%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.7 Hz), 7.57(1H, dd, J=4.8, 1.5 Hz),7.66(1H, dd, J=4.8, 3.0 Hz), 7.81-7.84(2H, m), 7.86(1H, s), 8.18(1H, d,J=2.1 Hz), 8.49(2H, s), 10.90(1H, s), 11.33(1H, s).

Example 76 Preparation of the Compound of Compound No. 74 (1)2-Benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide

5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(compound of Example 58(3); 4.81 g, 10 mmol) was dissolved intetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75 g, 10mmol) was added, and the mixture was stirred at room temperature for 12hours. The reaction mixture was poured into water and extracted withethyl acetate. After the organic layer was washed with aqueous sodiumhydrogen sulfite, water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=4:1),and recrystallized (ethyl acetate/n-hexane) to give the title compound(2.39 g, 42.7%) as a white solid.

¹H-NMR(DMSO-d₆): δ 4.91(2H, s), 5.36(2H, s), 7.32-7.35(3H, m), 7.47(1H,d, J=0.9 Hz), 7.52-7.56(2H, m), 7.82(1H, s), 8.21(1H, dd, J=8.7, 2.4Hz), 8.29(1H, d, J=2.4 Hz), 8.31(2H, s), 10.91(1H, s).

(2)2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide

A mixture of2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide(280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogencarbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour.The reaction mixture was poured into water, neutralized by sodiumhydrogen carbonate, and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(hexane:ethyl acetate=4:1) togive the title compound (181 mg, 67.5%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.72(3H, s), 5.29(2H, s), 7.33-7.36(3H, m), 7.40(1H,d, J=9.0 Hz), 7.54-7.57(2H, m), 7.81(1H, s), 7.94(1H, s), 8.12(1H, dd,J=8.7, 2.1 Hz), 8.27(1H, d, J=2.1 Hz), 8.31(2H, s), 10.86(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)benzamide(Compound No. 74)

2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl)benzamide(160 mg, 0.3 mmol) and 10% Pd—C (240 mg) were dissolved in ethanol (10ml) and stirred for 3.5 hours under hydrogen atmosphere. The reactionmixture was filtered and the filtrate was evaporated under reducedpressure to give the title compound (103.4 mg, 79.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.72(3H, s), 7.08(1H, d, J=8.7 Hz), 7.83(1H, s),7.85(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz), 8.42(1H, d, J=2.1 Hz),8.50(2H, s), 10.96(1H, s), 11.40(1H, s).

Example 77 Preparation of the Compound of Compound No. 75

A mixture of2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide(compound of Example 58(3); 280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg,0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10mL) was refluxed for 2 hours. After cooling, the reaction mixture waspoured into aqueous sodium hydrogen carbonate and extracted with ethylacetate. After the organic layer was washed with water and brine, driedover anhydrous magnesium sulfate, the residue obtained by evaporationunder reduced pressure was purified by chromatography on silicagel(n-hexane:ethyl acetate=1:2) to give a white solid (130.3 mg, 45.9%).Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C (11 mg),ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours underhydrogen atmosphere. The reaction mixture was filtered and the residueobtained by evaporation of the filtrate under reduced pressur waspurified by chromatography on silica gel(n-hexane:ethyl acetate=1:3) togive the title compound (18.3 mg, 20.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 6.90(1H, dt, J=6.6, 0.9 Hz), 7.10(1H, d, J=8.7 Hz),7.25(1H, m), 7.57(1H, d, J=9.0 Hz), 7.86(1H, s), 8.04(1H, dd, J=8.7, 2.1Hz), 8.35(1H, s), 8.48-8.56(4H, m), 11.00(1H, s), 11.41(1H, s).

Example 78 Preparation of the Compound of Compound No. 76 (1)N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (CompoundNo. 52; 4.75 g, 10 mmol), chloromethyl methyl ether (1.14 ml, 15 mmol),potassium carbonate (2.76 g, 20 mmol) and acetone (50 mL) was refluxedfor 8 hours. The reaction mixture was poured into diluted hydrochloricacid and extracted with ethyl acetate. After the organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, theresidue obtained by evaporation under reduced pressure was purified bychromatography on silica gel(n-hexane:ethyl acetate=3:1), andrecrystallized (n-hexane/ethyl acetate) to give the title compound (3.96g, 76.3%) as a white solid.

¹H-NMR(DMSO-d₆): δ 3.38(3H, s), 5.28(2H, s), 7.12(1H, d, J=9.0 Hz),7.81(1H, s), 7.82(1H, dd, J=8.7, 2.4 Hz), 7.88(1H, d, J=2.4 Hz),8.40(2H, s), 10.87(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide

N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide(0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 ml).Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) anddichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) wereadded, and the mixture was stirred at 100° C. for 1.5 hours. Aftercooling, the reaction mixture was poured into water and extracted withethyl acetate. After the organic layer was washed with water and brine,dried over anhydrous sodium sulfate, the residue obtained by evaporationunder reduced pressure was purified by chromatography on silicagel(n-hexane:ethyl acetate=2:1→1:1) to give the title compound (37.9 mg,20.8%) as a white powder.

¹H-NMR(CDCl₃): δ 3.64(3H, s), 5.53(2H, s), 7.23-7.28(1H, m),7.36(1H, d,J=8.7 Hz), 7.65(1H, s), 7.77-7.84(2H, m), 8.20(2H, s), 8.31(1H, dd,J=8.7, 2.4 Hz), 8.68-8.70(1H, m), 8.83(1H, d, J=2.4 Hz), 10.12(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)benzamide(Compound No. 76)

Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml) were addedtoN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)benzamide(37.9 mg, 0.08 mmol), and the mixture was refluxed for 2 hours. Aftercooling, the reaction mixture was poured into saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=2:1) togive the title compound (16.2 mg, 47.2%) as a white powder.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=8.4 Hz), 7.33(1H, ddd, J=7.5, 6.3, 1.2Hz), 7.86-7.91(2H, m), 7.97(1H, d, J=7.8 Hz), 8.20(1H, dd, J=8.7, 2.1Hz), 8.50(2H, s), 8.59(1H, d, J=2.4 Hz), 8.64-8.66(1H, m), 10.97(1H, s),11.53(1H, s).

Example 79 Preparation of the Compound of Compound No. 77

Using 5-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 56.8%.

¹H-NMR(DMSO-d₆): δ 3.77(3H, s), 6.97(1H, d, J=9.0 Hz), 7.10(1H, dd,J=9.0, 3.0 Hz), 7.43(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s),10.84(1H, s), 10.91(1H, s).

Example 80 Preparation of the Compound of Compound No. 79 (1)5-Acetyl-2-methoxybenzoic acid methyl ester

A mixture of 5-acetylsalicylic acid methyl ester (5.00 g, 25.7 mmol),sodium carbonate (7.10 g, 51.4 mmol) and N,N-dimethylformamide (25 mL)was cooled with ice bath. Methyl iodide (2.5 mL, 40.1 mmol) was added,and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was poured into water, neutralized by hydrochloricacid, and extracted with ethyl acetate. After the organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, theresidue obtained by evaporation under reduced pressure was washed undersuspension(isopropyl ether/n-hexane) to give the title compound (5.17 g,96.5%) as a white crystal.

¹H-NMR(CDCl₃): δ 2.59(3H, s), 3.92(3H, s), 3.99(3H, s), 7.04(1H, d,J=8.7 Hz), 8.12(1H, dd, J=8.7, 2.4 Hz), 8.41(1H, d, J=2.4 Hz).

(2) 5-Isobutyryl-2-methoxybenzoic acid methyl ester

A mixture of 5-acetyl-2-methoxybenzoic acid methyl ester (0.50 g, 2.40mmol), potassium tert-butoxide (0.81 g, 7.22 mmol) and tetrahydrofuran(10 mL) was cooled with ice bath. Methyl iodide (0.5 mL, 8.03 mmol) wasadded, and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured into water, neutralized by hydrochloricacid, and extracted with ethyl acetate. After the organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, theresidue obtained by evaporation under reduced pressure was purified bychromatography on silica gel(n-hexane:ethyl acetate=3:1→2:1) to give thetitle compound (143.1 mg, 25.2%) as a light yellow oil.

¹H-NMR(CDCl₃): δ 1.22(6H, d, J=6.9 Hz), 3.52(1H, m), 3.92(3H, s),3.98(3H, s), 7.05(1H, d, J=8.7 Hz), 8.13(1H, dd, J=8.7, 2.4 Hz),8.42(1H, d, J=2.4 Hz).

(3) 5-Isobutyryl-2-methoxybenzoic acid

5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol)was dissolved in methanol (5 mL). 2N Aqueous sodium hydroxide (1 ml) wasadded, and the mixture was refluxed for 1 hour. After cooling, thereaction mixture was poured into 2N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate, and evaporated under reduced pressure togive the title compound (134 mg, yield: quantitative) as a whitecrystal.

¹H-NMR(CDCl₃): δ 1.22(6H, d, J=6.9 Hz), 3.59(1H, m), 4.15(3H, s),7.16(1H, d, J=8.7 Hz), 8.24(1H, dd, J=8.7, 2.4 Hz), 8.73(1H, d, J=2.1Hz).

(4) 5-Isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide

Using 5-isobutyryl-2-methoxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 61.4%.

¹H-NMR(CDCl₃): δ 1.23(6H, d, J=6.9 Hz), 3.64(1H, m), 4.20(3H, s),7.18(1H, d, J=8.7 Hz), 7.65(1H, s), 8.19(2H, s), 8.22(1H, dd, J=8.7, 2.1Hz), 8.88(1H, d, J=2.1 Hz), 9.98(1H, s).

(5) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide(Compound No. 79)

A mixture of5-isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide(143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reactionmixture was poured into 2N hydrochloric acid and extracted with ethylacetate. After the organic layer was washed with brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was purified by chromatography on silicagel(n-hexane:ethyl acetate=3:1) and crystallized (ethylacetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) asa white crystal.

¹H-NMR(DMSO-d₆): δ 1.12(6H, d, J=6.9 Hz), 3.66(1H, m), 7.12(1H, d, J=8.4Hz), 7.85(1H, s), 8.07(1H, dd, J=8.4, 2.4 Hz), 8.45(1H, d, J=2.4 Hz),8.47(2H, s), 10.93(1H, s), 11.95(1H, brs).

Example 81 Preparation of the Compound of Compound No. 81

Using 4-hydroxyisophthalic acid 1-methyl ester and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 91.5%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.12(1H, d, J=8.4 Hz), 7.86(1H, s),8.02(1H, dd, J=8.7, 2.4 Hz), 8.46-8.47(3H, m), 10.96(1H, s), 12.03(1H,brs).

[4-Hydroxyisophthalic acid 1-methyl ester: Refer to “Journal of theChemical Society”, (England), 1956, p. 3099-3107.]

Example 82 Preparation of the Compound of Compound No. 80

N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methylester (Comound No. 81; 2.85 g, 7 mmol) was suspended in a mixed solventof methanol (14 mL) and tetrahydrofuran (14 mL). 2N Aqueous sodiumhydroxide (14 mL) was added, and the mixture was refluxed for 2 hours.After cooling, 2N hydrochloric acid (20 ml) was added to the reactionmixture and the separated solid was filtered, washed with water, driedto give the title compound (2.68 g, 97.4%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.10(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s),8.01(1H, dd, J=8.7, 2.4 Hz), 8.47(2H, s), 8.48(1H, d, J=2.4 Hz),10.97(1H, s), 11.98(1H, brs).

When the method described in Example 82 is referred in the followingexamples, inorganic bases such as sodium hydroxide, potassium carbonateor the like were used as the base. As the reaction solvent, solventssuch as water, methanol, ethanol, tetrahydrofuran or the like were usedalone or as a mixture.

Example 83 Preparation of the Compound of Compound No. 82

Using 4-hydroxyisophthalic acid (182 mg, 1 mmol),3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorustrichloride (87 μl; 1 mmol) and toluene (10 mL), the same operation asthe Example 16 gave the title compound (151 mg, 25.0%) as a whitecrystal.

¹H-NMR(DMSO-d₆): δ 7.18(1H, d, J=8.7 Hz), 7.82(1H, s), 7.86(1H, s),8.11(1H, dd, J=8.7, 2.4 Hz), 8.50(2H, s), 8.54(2H, s), 8.56(1H, d, J=2.4Hz), 10.79(1H, s), 10.99(1H, s), 11.84(1H, brs).

Example 84 Preparation of the Compound of Compound No. 83 (1)4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid methylester

Sodium hydride (60%; 1.04 g, 26 mmol) was washed with n-hexane, andsuspended in N,N-dimethylformamide (100 mL). A solution ofN-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methylester (Compound No. 81; 8.15 g, 20 mmol) in N,N-dimethylformamide (100mL) was added dropwise under cooling with ice bath. After the additionwas finished, the mixture was stirred at room temperature for 1 hour. Asolution of benzyl bromide (4.45 g, 26 mmol) in N,N-dimethylformamide(10 mL) was added, and the mixture was stirred at 60° C. for 3 hours.After cooling, the reaction mixture was poured into ice and water, andextracted with ethyl acetate. After the organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate, the residueobtained by evaporation under reduced pressure was recrystallized (ethylacetate/n-hexane) to give the title compound (5.38 g, 54.1%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 3.87(3H, s), 5.33(2H, s), 7.33-7.36(3H, m), 7.46(1H,d, J=8.7 Hz), 7.53-7.56(2H, m), 7.82(1H, s), 8.15(1H, dd, J=8.7, 2.1Hz), 8.25(1H, d, J=2.1 Hz)8.28(2H, s), 10.87(1H, s).

(2) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acidmethyl ester as the raw material, the same operation as the Example 82gave the title compound.

Yield: 79.7%.

¹H-NMR(DMSO-d₆): δ 5.32(2H, s), 7.32-7.34(3H, m), 7.43(1H, d, J=8.7 Hz),7.52-7.56(2H, m), 7.81(1H, s), 8.12(1H, dd, J=8.7, 2.1 Hz), 8.22(1H, d,J=2.1 Hz), 8.28(2H, s), 10.85(1H, s), 13.81(1H, brs).

(3)4-Benzyloxy-N³-[3,5-bis(trifluoromethyl)phenyl]—N¹,N¹-dimethylisophthalamide

WSC.HCl (95 mg, 0.50 mmol) was added to a solution of4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (242mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol) andtriethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL) under icecooling, and the mixture was stirred at room temperature for 3 hours.The reaction mixture was poured into water and extracted with ethylacetate. After the organic layer was washed with diluted hydrochloricacid, water and brine, dried over anhydrous magnesium sulfate, theresidue obtained by evaporation of the solvent under reduced pressurewas purified by chromatography on silica gel(hexane:ethyl acetate=1:4)to give the title compound (165 mg, 64.9%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.99(6H, s)5.29(2H, s), 7.32-7.38(4H, m),7.52-7.56(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz), 7.73(1H, d, J=2.1 Hz),7.80(1H, s), 8.28(2H, s), 10.83(1H, s).

When the method described in Example 84(3) is referred in the followingexamples, organic bases such as pyridine, triethylamine or the like wereused as the base. As the reaction solvent, solvents such asdichloromethane, tetrahydrofuran or the like were used alone or as amixture.

(4)N³-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N¹,N¹-dimethylisophthalamide(Compound No. 83)

A solution of4-benzyloxy-N³-[3,5-bis(trifluoromethyl)phenyl]-N¹,N¹-dimethyl-isophthalamide(141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in a mixed solvent of ethanol (5ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hourunder hydrogen atmosphere. The reaction mixture was filtered and thefiltrate was evaporated under reduced pressure to give the titlecompound (106 mg, 91.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.98(6H, s), 7.02(1H, d, J=8.7 Hz), 7.52(1H, dd,J=8.7, 2.1 Hz), 7.84(1H, s), 7.95(1H, d, J=2.1 Hz), 8.46(2H, s),11.10(1H, brs), 11.63(1H, brs).

Example 85 Preparation of the Compound of Compound No. 84 (1)2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)-benzamide

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid(compound of Example 84(2)) and piperidine as the raw materials, thesame operation as the Example 84(3) gave the title compound.

Yield: 56.4%.

¹H-NMR(CDCl₃): δ 1.53-1.70(6H, m), 3.44(2H, brs), 3.70(2H, brs),5.26(2H, s), 7.24(1H, d, J=8.7 Hz), 7.26(1H, s), 7.52-7.58(5H, m),7.66(2H, s), 7.74(1H, dd, J=8.7, 2.4 Hz), 8.37(1H, d, J=2.1 Hz),10.27(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)benzamide(Compound No. 84)

Using2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)benzamideas the raw material, the same operation as the Example 84(4) gave thetitle compound.

Yield: 96.3%, white solid.

¹H-NMR(DMSO-d₆): δ 1.51(4H, brs), 1.60-1.65(2H, m), 3.47(4H, brs),7.04(1H, d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz), 7.85(1H, s),7.92(1H, d, J=2.1 Hz), 8.46(2H, s), 10.99(1H, s), 11.64(1H, brs).

Example 86 Preparation of the Compound of Compound No. 85 (1)2-Benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide

Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid(compound of Example 84(2)) and 4-benzylpiperidine as the raw materials,the same operation as the Example 84(3) gave the title compound.

Yield: 76.7%.

¹H-NMR(CD₃OD): δ 1.18-1.38(2H, m), 1.67(1H, brs), 1.74(1H, brs),1.84-1.93(1H, m), 2.60(2H, d, J=7.2 Hz), 2.83(1H, brs), 3.10(1H, brs),3.78(1H, brs), 4.59(1H, brs), 5.34(2H, s), 7.15-7.18(3H, m),7.24-7.28(2H, m), 7.40-7.46(4H, m), 7.57-7.63(3H, m), 7.65(1H, dd,J=8.7, 2.4 Hz), 7.96(2H, s), 8.05(1H, d, J=2.1 Hz).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-carbonyl)-benzamide(Compound No. 85)

Using2-benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)phenyl]-benzamideas the raw material, the same operation as the Example 84(4) gave thetitle compound.

Yield: 54.3%, white solid.

¹H-NMR(DMSO-d₆): δ 1.08-1.22(2H, m), 1.59-1.62(2H, m), 1.77-1.80(1H, m),2.50-2.55(2H, m), 2.87(2H, brs), 3.75(1H, br), 4.39(1H, br), 7.06(1H, d,J=8.4 Hz), 7.17-7.20(3H, m), 7.28(2H, t, J=7.2 Hz), 7.49(1H, dd, J=8.4,2.1 Hz), 7.84(1H, s), 7.93(1H, d, J=2.1 Hz), 8.47(2H, s), 10.89(1H, s),11.65(1H, s).

Example 87 Preparation of the Compound of Compound No. 86 (1)2-Methoxy-5-sulfamoylbenzoic acid

Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was dissolved inmethanol (30 mL). 2N Aqueous sodium hydroxide (30 mL, 60 mmol) wasadded, and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured into 2N hydrochloric acid, and the separatedsolid was filtered to give the title compound (4.55 g, 98.3%) as a whitesolid.

¹H-NMR(DMSO-d₆): δ 3.89(3H, s), 7.30(1H, d, J=8.7 Hz), 7.32(2H, s),7.92(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d, J=2.7 Hz), 13.03(1H, br).

(2) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sufamoylbenzamide

Using 2-methoxy-5-sulfamoylbenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 24 gave the title compound.

Yield: 24.2%.

¹H-NMR(DMSO-d₆): δ 3.97(3H, s), 7.38(2H, s), 7.39(1H, d, J=8.7 Hz),7.85(1H, s), 7.96(1H, dd, J=8.7, 2.4 Hz), 8.06(1H, d, J=2.4 Hz),8.43(2H, s), 10.87(1H, s).

(3)N-[3,5-Bis(trifluoromethyl)phenyl)-5-dimethylsufamoyl-2-methoxybenzamide

A suspension ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sufamoylbenzamide (442mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol) and sodium carbonate(415 mg, 3.0 mmol) in acetonitrile (10 mL) was refluxed for 3 hours.After cooling to room temperature, the reaction mixture was poured intowater and extracted with ethyl acetate. After the organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, theresidue obtained by evaporation of the solvent under reduced pressurewas recrystallized from a mixed solvent of n-hexane and ethyl acetate(2:1) to give the title compound (207 mg, 44.1%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.62(6H, s), 3.99(3H, s), 7.45(1H, d, J=9.0 Hz),7.85(1H, s), 7.91(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=2.4 Hz)8.43(2H,s), 10.90(1H, s).

(4)N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsufamoyl-2-hydroxybenzamide(Compound No. 86)

UsingN-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylsufamoyl-2-methoxybenzamideas the raw material, the same operation as the Example 80(5) gave thetitle compound.

Yield: 45.5%.

¹H-NMR(DMSO-d₆): δ 2.61(6H, s), 7.20(1H, d, J=8.7 Hz), 7.77(1H, dd,J=8.7, 2.1 Hz), 7.86(1H, s), 8.14(1H, d, J=2.1 Hz)8.45(2H, s), 11.16(1H,s), 12.15(1H, br).

Example 88 Preparation of the Compound of Compound No. 87 (1)N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzamide

A mixture ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide(compound of Example 87(2); 442 mg, 1 mmol),2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5 mL)was refluxed for 2 hours. After cooling, the reaction mixture was pouredinto water and extracted with ethyl acetate. After the organic layer waswashed with water, saturated aqueous sodium hydrogen carbonate andbrine, dried over anhydrous magnesium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified bychromatography on silica gel(n-hexane:ethyl acetate=3:2) to give thetitle compound (436.5 mg, 88.6%) as a white solid.

¹H-NMR(DMSO-d₆): δ 3.96(3H, s), 6.36(2H, dd, J=2.4, 2.1 Hz), 7.37(2H,dd, J=2.4, 2.1 Hz), 7.42(1H, d, J=9.0 Hz), 7.85(1H, s), 8.80(1H, dd,J=9.0, 2.4 Hz)8.18(1H, d, J=2.7 Hz), 8.38(2H, s), 10.92(1H, s).

(2)N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)benzamide(Compound No. 87)

UsingN-[3,5-bis(trifluoromethyl)phenyl)-2-methoxy-5-(pyrrole-1-sulfonyl)benzamideas the raw material, the same operation as the Example 80(5) gave thetitle compound.

Yield: 79.4%.

¹H-NMR(DMSO-d₆): δ 6.36(2H, dd, J=2.4, 2.1 Hz), 7.18(1H, d, J=9.0 Hz),7.34(2H, dd, J=2.4, 2.1 Hz), 7.86(1H, s), 7.99(1H, dd, J=9.0, 2.7Hz)8.31(1H, d, J=2.7 Hz), 8.42(2H, s), 10.98(1H, s).

Example 89 Preparation of the Compound of Compound No. 88

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide(Compound No. 53) as the raw material, the same operation as the Example84(4) gave the title compound.

Yield: 98.0%.

¹H-NMR(DMSO-d₆): δ 4.79(2H, brs), 6.76(1H, d, J=2.1 Hz), 6.76(1H, s),7.09(1H, dd, J=2.1, 1.2 Hz), 7.80(1H, s), 8.45(2H, s), 10.30(1H, br),10.84(1H, s).

Example 90 Preparation of the Compound of Compound No. 89

Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 28.8%.

¹H-NMR(DMSO-d₆): δ 2.85(6H, s), 6.92(1H, d, J=9.0 Hz), 7.01(1H, dd,J=8.7, 3.0 Hz), 7.22(1H, d, J=3.0 Hz), 7.84(1H, s), 8.47(2H, s),10.62(1H, s), 10.83(1H, s).

Example 91 Preparation of the Compound of Compound No. 90

Under argon atmosphere, a mixture of5-amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide (CompoundNo. 88; 364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and tetrahydrofuran(10 mL) was cooled on ice. Benzoyl chloride (155 mg, 1.1 mmol) wasadded, and the mixture was stirred for 1 hour. The reaction mixture waspoured into water and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) togive the title compound (121 mg, 25.7%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.51-7.62(3H, m), 7.81(1H, dd,J=8.7, 2.4 Hz), 7.83(1H, s), 7.98(2H, d, J=7.2 Hz), 8.22(1H, d, J=2.4Hz), 8.49(2H, s), 10.27(1H, s), 10.89(1H, s), 11.07(1H, s).

Example 92 Preparation of the Compound of Compound No. 91

5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (CompoundNo. 88; 100.2 mg, 0.28 mmol) was dissolved in acetonitrile (4 ml).4-Dimethylaminopyridine (3 mg) and phenylisocyanate (30 μl, 0.28 mmol)were added, and the mixture was stirred at 60° C. for 5 minutes. Thereaction mixture was concentrated and the residue was purified bychromatography on silica gel(n-hexane:ethyl acetate=1:1) to give thetitle compound (54.8 mg, 41.2%) as a light brown solid.

¹H-NMR(DMSO-d₆): δ 6.93-6.98(1H, m), 6.97(1H, d, J=9.3 Hz),7.27(2H, t,J=7.8 Hz), 7.34-7.46(2H, m), 7.50(1H, dd, J=9.0, 2.4 Hz), 7.83(1H, s),7.88(1H, s), 8.47(2H, s), 8.56(1H, s), 8.63(1H, s), 10.87(1H, s),10.89(1H, s).

Example 93 Preparation of the Compound of Compound No. 92

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 88) and phenylisothiocyanate as the raw materials, thesame operation as the Example 92 gave the title compound.

Yield: 66.3%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.4 Hz), 7.13(1H, tt, J=7.5, 1.2Hz),7.34(2H, t, J=7.8 Hz), 7.45-7.51(3H, m), 7.84(1H, s), 7.87(1H, d,J=2.7 Hz), 8.47(2H, s), 9.65(1H, s), 9.74(1H, s), 10.84(1H, s),11.32(1H, s).

Example 94 Preparation of the Compound of Compound No. 93

Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 11.3%.

¹H-NMR(DMSO-d₆): δ 7.23(1H, d, J=9.0 Hz), 7.87(1H, s),8.06(2H, d, J=9.0Hz), 8.10(1H, dd, J=9.0, 2.4 Hz), 8.44(2H, d, J=9.0 Hz), 8.50(2H, s),8.53(1H, d, J=2.4 Hz), 11.13(1H, s), 12.14(1H, br).

Example 95 Preparation of the Compound of Compound No. 94

Using 5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 7.9%.

¹H-NMR(DMSO-d₆): δ 6.87(1H, t, J=6.0 Hz), 7.22(1H, d, J=8.7 Hz),7.21-7.23(1H, m), 7.77(1H, t, J=8.4 Hz), 7.87(1H, s), 7.95-7.98(3H, m),8.03-8.07(4H, m), 8.47(1H, d, J=2.4 Hz), 8.49(2H, s), 11.14(1H, s),12.03(1H, br).

Example 96 Preparation of the Compound of Compound No. 96

N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (CompoundNo. 50; 1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) were dissolvedin tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was addeddropwise under ice cooling, and the mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated under reducedpressure. 2 N hydrochloric acid was added to the residue, and it wasextracted with ethyl acetate. After the ethyl acetate layer was washedwith water and brine, dried over anhydrous magnesium sulfate andconcentrated, the residue was recrystallized from n-hexane/ethyl acetateto give the title compound (1.06 g, 83.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 2.22(3H, s), 7.35(1H, d, J=9.0 Hz), 7.71(1H, dd,J=8.7, 2.7 Hz), 7.85(1H, s), 7.88(1H, d, J=2.7 Hz), 8.37(2H, s),11.05(1H, brs).

When the method described in Example 96 is referred in the followingexamples, organic bases such as pyridine, triethylamine or the like wereused as the base. As the reaction solvent, solvents such asdichloromethane, tetrahydrofuran, benzene or the like were used alone oras a mixture.

Example 97 Preparation of the Compound of Compound No. 97 (1)4-Acetylamino-5-chloro-2-methoxybenzoic acid

Using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl ester as theraw material, the same operation as the Example 82 gave the titlecompound.

Yield: 88.0%.

¹H-NMR(DMSO-d₆): δ 2.16(3H, s), 3.78(3H, s), 7.72(1H, s), 7.77(1H, s),9.57(1H, s), 12.74(1H, s).

(2)4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide

Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 24 gave the title compound.

Yield: 23.8%.

¹H-NMR(DMSO-d₆): δ 2.17(3H, s), 3.89(3H, s), 7.77-7.82(3H, m),8.45-8.49(2H, m), 9.66(1H, s), 10.68(1H, s).

(3)4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydoxybenzamide(Compound No. 97)

Using4-acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamideas the raw material, the same operation as the Example 80(5) gave thetitle compound.

Yield: 72.8%.

¹H-NMR(DMSO-d₆): δ 2.17(3H, s), 7.75(1H, s), 7.82(1H, s), 7.95(1H, s),8.44(2H, s), 9.45(1H, s), 11.16(1H, brs), 11.63(1H, brs).

Example 98 Preparation of the Compound of Compound No. 98

Using 4-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 55.8%.

¹H-NMR(DMSO-d₆): δ 7.05-7.08(2H, m), 7.84-7.87(2H, m), 8.45(2H, s),10.84(1H, s)11.64(1H, brs).

Example 99 Preparation of the Compound of Compound No. 99

Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)-2-bromoanilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 14.5%.

¹H-NMR(DMSO-d₆): δ 7.11(1H, d, J=9.0 Hz), 7.53(1H, dd, J=9.0, 2.7 Hz),7.91(1H, d, J=1.8 Hz), 7.98(1H, d, J=2.7 Hz), 9.03(1H, d, J=1.8 Hz),11.26(1H, brs).

Example 100 Preparation of the Compound of Compound No. 100

Using 5-chlorosalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 3.6%.

¹H-NMR(CDCl₃): δ 7.03(1H, d, J=8.7 Hz), 7.43-7.48(2H, m), 6.61(1H, d,J=8.1 Hz), 7.85(1H, d, J=8.4 Hz), 8.36(1H, br s), 8.60(1H, s), 11.31(1H,s).

Example 101 Preparation of the Compound of Compound No. 101

Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 24.0%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.65(1H, dd, J=8.7, 2.7 Hz),7.76(1H, d, J=8.4 Hz), 8.03(1H, d, J=8.1 Hz)8.11(1H, d, J=2.7 Hz),8.74(1H, s), 11.02(1H, s), 12.34(1H, s).

Example 102 Preparation of the Compound of Compound No. 102

Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 1.5%.

¹H-NMR(CDCl₃): δ 2.36(3H, s), 6.97(1H, d, J=8.4 Hz), 7.23(1H, s),7.32(1H, dd, J=8.4, 1.5 Hz), 7.57(1H, d, J=8.4 Hz), 7.83(1H, d, J=8.4Hz), 8.46(1H, s), 8.69(1H, s), 11.19(1H, s).

Example 103 Preparation of the Compound of Compound No. 103

Using N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide(Compound No. 100) and acetyl chloride as the raw materials, the sameoperation as the Example 96 gave the title compound.

Yield: 6.6%.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 7.17(1H, d, J=8.7 Hz),7.54(1H, dd, J=8.7,2.4 Hz), 7.55(1H, d, J=8.1 Hz), 7.80(1H, d, J=8.1 Hz), 7.95(1H, d, J=2.4Hz), 8.60(1H, s), 8.73(1H, s).

Example 104 Preparation of the Compound of Compound No. 104

Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 58.0%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.42(1H, t, J=7.5 Hz),7.52(1H, dd, J=8.7, 2.7 Hz), 7.74(1H, t, J=8.1 Hz), 7.77(1H, t, J=8.1Hz), 7.99(1H, d, J=2.7 Hz), 8.18(1H, d, J=8.1 Hz), 10.76(1H, s),12.22(1H, s).

Example 105 Preparation of the Compound of Compound No. 105

Using 5-chlorosalicylic acid and 4-chloro-2-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 21.5%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.80-7.85(2H, m), 7.97(1H, d, J=2.7 Hz), 8.26(1H, d, J=8.4 Hz),10.80(1H, s), 12.26(1H, s).

Example 106 Preparation of the Compound of Compound No. 106

Using 5-bromosalicylic acid and 3-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 50.3%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.48-7.52(1H, m), 7.59(1H, dd,J=8.7, 2.7 Hz), 7.62(1H, t, J=8.1 Hz), 7.92-7.96(1H, m), 8.02(1H, d,J=2.4 Hz), 8.20(1H, s), 10.64(1H, s), 11.60(1H, s).

Example 107 Preparation of the Compound of Compound No. 107

Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 71.7%, white solid.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=9.0 Hz), 7.46(1H, t, J=7.8 Hz),7.52(1H, dd, J=9.0, 2.7 Hz), 7.58(1H, t, J=7.2 Hz), 7.96(1H, d, J=2.7Hz), 8.49(1H, t, J=7.2 Hz), 10.82(1H, s), 12.13(1H, brs).

Example 108 Preparation of the Compound of Compound No. 108

Using 5-chlorosalicylic acid and 4-fluoro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 72.1%, white solid.

¹H-NMR(DMSO-d₆):7.03(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.56(1H, d, J=9.9 Hz), 7.90(1H, d, J=2.7 Hz), 7.99-8.03(1H, m), 8.21(1H,dd, J=6.6, 2.4 Hz), 10.63(1H, s), 11.58(1H, s).

Example 109 Preparation of the Compound of Compound No. 109

Using 5-bromosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 37.4%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.59(1H, dd, J=8.7, 2.4 Hz),7.73(1H, d, J=8.7 Hz), 7.98(1H, d, J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4Hz), 8.31(1H, d, J=2.4 Hz), 10.68(1H, s), 11.52(1H, brs).

Example 110 Preparation of the Compound of Compound No. 110

Using 5-chlorosalicylic acid and 3-fluoro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 62.0%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.42(1H, d, J=8.4 Hz),7.48(1H, dd, J=9.0, 3.0 Hz), 7.85(1H, d, J=2.4 Hz), 7.94(1H, dd, J=11.4,2.1 Hz), 7.99(1H, s), 10.73(1H, s), 11.46(1H, s).

Example 111 Preparation of the Compound of Compound No. 111

Using 5-bromosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 73.3%.

¹H-NMR(DMSO-d₆): δ 6.99(1H, d, J=9.0 Hz), 7.60(1H, dd, J=9.0, 2.4 Hz),7.72(1H, s), 7.97(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H,s), 11.45(1H, s).

Example 112 Preparation of the Compound of Compound No. 112

Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 77.9%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=9.0 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz),7.58-7.61(2H, m), 7.95(1H, d, J=2.7 Hz), 8.71(1H, d, J=7.5 Hz),10.90(1H, s), 12.23(1H, s).

Example 113 Preparation of the Compound of Compound No. 113

Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 49.1%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz),7.55(1H, dd, J=8.4, 2.7 Hz), 7.83(1H, d, J=8.4 Hz), 7.98(1H, d, J=3.0Hz), 8.88(1H, d, J=2.7 Hz), 11.14(1H, s), 12.39(1H, s).

Example 114 Preparation of the Compound of Compound No. 114

Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 34.2%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.56(1H, ddd, J=8.1, 2.4, 1.2Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.83(1H, dd, J=8.1, 1.2 Hz), 8.11(1H,d, J=2.7 Hz), 8.87(1H, d, J=2.4 Hz), 11.12(1H, s), 12.42(1H, s).

Example 115 Preparation of the Compound of Compound No. 115

Using 5-chlorosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.7 Hz),7.81(1H, d, J=2.7 Hz), 8.23-8.24(2H, m), 8.43(1H, d, J=1.2 Hz),11.02(1H, S), 11.30(1H, br).

Example 116 Preparation of the Compound of Compound No. 116

Using 5-chlorosalicylic acid and 2-nitro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 8.1%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.73(1H, dd, J=8.4, 1.8 Hz), 7.95(1H, d, J=3.0 Hz), 8.36(1H, d, J=8.7Hz), 9.01(1H, d, J=1.8 Hz), 12.04(1H, s), 12.20(1H, s).

Example 117 Preparation of the Compound of Compound No. 117

Using 5-bromosalicylic acid and 4-cyano-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 49.7%.

¹H-NMR(DMSO-d₆): δ 6.99(1H, d, J=8.7 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz),7.92(1H, d, J=2.7 Hz), 8.16(2H, s), 8.42(1H, s), 10.93(1H, s), 11.36(1H,s).

Example 118 Preparation of the Compound of Compound No. 118

Using 5-chlorosalicylic acid and 2-methyl-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 14.5%.

¹H-NMR(DMSO-d₆): δ 2.36(3H, d, J=1.2 Hz), 7.05(1H, d, J=8.7 Hz),7.46(1H, t, J=8.1 Hz), 7.50(1H, dd, J=8.7, 2.7 Hz), 7.60(1H, d, J=7.2Hz), 7.99(1H, d, J=7.2 Hz), 8.00(1H, d, J=2.4 Hz), 10.43(1H, s),12.08(1H, s).

Example 119 Preparation of the Compound of Compound No. 119

Using 5-chlorosalicylic acid and 4-methyl-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 80.2%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=8.7 Hz), 7.44(1H, d, J=8.4 Hz),7.47(1H, dd, J=9.0, 2.7 Hz), 7.84(1H, dd, J=8.4, 2.1 Hz), 7.92(1H, d,J=2.7 Hz), 8.13(1H, d, J=2.1 Hz), 10.65(1H, s), 11.68(1H, br).

Example 120 Preparation of the Compound of Compound No. 120

Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 73.3%.

¹H-NMR(DMSO-d₆): δ 2.39(3H, s), 7.07(1H, d, J=8.7 Hz), 7.44-7.54(3H, m),7.99(1H, d, J=3.0 Hz), 8.43(1H, s), 10.52(1H, s), 12.17(1H, brs).

Example 121 Preparation of the Compound of Compound No. 121

Using 5-chlorosalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 79.1%.

¹H-NMR(DMSO-d₆): δ 3.89(3H, s), 7.02(1H, d, J=9.0 Hz), 7.30(1H, d, J=9.0Hz), 7.48(1H, dd, J=9.0, 3.0 Hz), 7.92(1H, dd, J=9.0, 2.4 Hz), 7.96(1H,d, J=2.7 Hz), 8.04(1H, d, J=2.4 Hz), 10.47(1H, s), 11.78(1H, s).

Example 122 Preparation of the Compound of Compound No. 122

Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 58.8%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 6.98(1H, d, J=8.7 Hz), 7.03(1H, s),7.57-7.61(2H, m), 7.77(1H, s), 8.00(1H, d, J=2.4 Hz), 10.57(1H, s),11.56(1H, s).

Example 123 Preparation of the Compound of Compound No. 123

Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 71.3%.

¹H-NMR(DMSO-d₆): δ 3.99(3H, s), 7.03(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7Hz), 7.47-7.51(1H, m), 7.61(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4Hz), 8.82(1H, d, J=2.1 Hz)11.03(1H, s), 12.19(1H, s).

Example 124 Preparation of the Compound of Compound No. 124

Using 5-chlorosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 83.4%.

¹H-NMR(DMSO-d₆): δ 4.00(3H, s), 7.08(1H, d, J=9.0 Hz), 7.30(1H, d, J=8.7Hz), 7.47-7.52(2H, m), 7.97(1H, d, J=2.7 Hz), 8.83(1H, d, J=2.4 Hz),11.05(1H, s), 12.17(1H, s).

Example 125 Preparation of the Compound of Compound No. 125

Using 5-chlorosalicylic acid and2-methylsulfanyl-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 79.2%.

¹H-NMR(DMSO-d₆): δ 2.57(3H, s), 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd,J=8.7, 2.4 Hz), 7.55(1H, dd, J=8.4, 1.5 Hz), 7.63(1H, d, J=8.1 Hz),8.00(1H, d, J=2.4 Hz), 8.48(1H, d, J=1.5 Hz), 10.79(1H, s), 12.26(1H,s).

Example 126 Preparation of the Compound of Compound No. 126

Using 5-bromosalicylic acid and2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 44.5%.

¹H-NMR(DMSO-d₆): δ 1.86-1.91(4H, m), 3.20-3.26(4H, m), 6.99(1H, d, J=8.7Hz), 7.07(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 2.1 Hz), 7.62(1H, dd,J=8.7, 2.4 Hz), 7.94(1H, d, J=2.1 Hz), 8.17(1H, d, J=2.4 Hz), 10.54(1H,s), 12.21(1H, s).

Example 127 Preparation of the Compound of Compound No. 12

Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 65.9%.

¹H-NMR(DMSO-d₆): δ 2.90(4H, dd, J=4.5, 4.2 Hz), 3.84(4H, dd, J=4.8, 4.2Hz), 7.09(1H, d, J=8.4 Hz), 7.48(2H, s), 7.61(1H, dd, J=8.4, 2.7 Hz),8.13(1H, d, J=2.7 Hz), 8.90(1H, s), 11.21(1H, s), 12.04(1H, s).

Example 128 Preparation of the Compound of Compound No. 128

Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 75.0%, white solid

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.74(2H, d, J=8.7 Hz), 7.90(1H, d, J=2.7 Hz), 7.95(2H, d, J=9.0 Hz),10.65(1H, s), 11.59(1H, s).

Example 129 Preparation of the Compound of Compound No. 129

Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 34.9%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz),7.79(1H, dd, J=9.0, 2.1 Hz), 7.99(1H, d, J=2.1 Hz), 8.11(1H, d, J=2.4Hz), 8.73(1H, d, J=9.0 Hz), 11.15(1H, s), 12.42(1H, s).

Example 130 Preparation of the Compound of Compound No. 130

Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 113) and acetyl chloride as the raw materials, the sameoperation as the Example 96 gave the title compound.

Yield: 34.0%.

¹H-NMR(CDCl₃): δ 2.39(3H, s), 7.16(1H, d, J=8.7 Hz),7.37(1H, ddd, J=8.7,2.4, 0.6 Hz), 7.51-7.56(2H, m), 7.97(1H, d, J=3.0 Hz), 8.85(1H, s),8.94(1H, d, J=1.8 Hz).

Example 131 Preparation of the Compound of Compound No. 131

Using 5-nitrosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 31.1%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=9.3 Hz), 7.52(1H, dd, J=8.4, 2.1 Hz),7.81(1H, d, J=8.4 Hz), 8.21(1H, dd, J=9.0, 3.3 Hz), 8.82(1H, d, J=3.0Hz), 8.93(1H, d, J=2.4 Hz), 12.18(1H, s).

Example 132 Preparation of the Compound of Compound No. 132

Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 15.8%.

¹H-NMR(CDCl₃): δ 2.36(3H, s), 6.95(1H, d, J=8.1 Hz), 7.26-7.31(2H, m),7.37(1H, dd, J=8.4, 1.8 Hz), 7.56(1H, d, J=8.4 Hz), 8.65(1H, br s),8.80(1H, d, J=1.8 Hz), 11.33(1H, br s).

Example 133 Preparation of the Compound of Compound No. 133

Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 56.4%.

¹H-NMR(DMSO-d₆): δ 3.77(3H, s), 6.91(1H, d, J=9.0 Hz), 7.07(1H, dd,J=8.7, 3.0 Hz), 7.20(1H, t, J=1.8 Hz), 7.52-7.54(3H, m), 10.33(1H, s),11.44(1H, s).

Example 134 Preparation of the Compound of Compound No. 134

Using 5-methylsalicylic acid and 4-chloro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 70.4%.

¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 6.91(1H, d, J=8.3 Hz), 7.27(1H, ddd,J=8.3, 2.2, 0.6 Hz), 7.71(1H, d, J=2.2 Hz), 7.72(1H, d, J=8.5 Hz),8.02(1H, dd, J=8.5, 2.5 Hz), 8.33(1H, d, J=2.5 Hz), 10.64(1H, s),11.25(1H, s).

Example 135 Preparation of the compound of Compound No. 135

Using 5-methylsalicylic acid and 4-methyl-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 63.7%.

¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 2.42(3H, s), 6.89(1H, d, J=8.4 Hz),7.26(1H, ddd, J=8.4, 2.1, 0.6 Hz), 7.44(1H, d, J=8.1 Hz), 7.75(1H, d,J=2.1 Hz), 7.86(1H, dd, J=8.4, 1.8 Hz), 8.13(1H.d, J=2.1 Hz), 10.50(1H,s), 11.42(1H, s).

Example 136 Preparation of the Compound of Compound No. 136

Using 5-methylsalicylic acid and 2-methyl-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 14.2%, white solid.

¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 2.38(3H, s), 6.94(1H, d, J=8.4 Hz),7.27(1H, ddd, J=8.4, 2.4, 0.6 Hz), 7.44(1H, dd, J=8.1, 1.5 Hz), 7.52(1H,d, J=7.8 Hz), 7.84(1H, d, J=2.4 Hz), 8.46(1H, d, J=1.5 Hz), 10.55(1H,s), 11.72(1H, s).

Example 137 Preparation of the Compound of Compound No. 137

Using 5-methylsalicylic acid and 4-methoxy-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 65.1%, slightly yellow solid.

¹H-NMR(DMSO-d₆): δ 2.35(3H, s), 3.89(3H, s), 6.88(1H, d, J=8.4 Hz),7.26(1H, dd, J=8.1, 1.8 Hz), 7.30(1H, d, J=8.4 Hz), 7.77(1H, d, J=2.1Hz), 7.92(1H, dd, J=9.0, 2.7 Hz), 8.04(1H, d, J=2.7 Hz), 10.42(1H, s),11.54(1H, s).

Example 138 Preparation of the Compound of Compound No. 138

Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 77.9%.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 4.02(3H, s), 6.93(1H, d, J=9.0 Hz),6.98(1H, d, J=8.4 Hz), 7.25-7.28(2H, m), 7.36(1H, ddd, J=8.4, 2.1, 0.9Hz), 8.65(1H, br s), 8.73(1H, d, J=2.1 Hz), 11.69(1H, s).

Example 139 Preparation of the Compound of Compound No. 139

Using 5-bromosalicylic acid and aniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 68.8%.

mp 229-230° C.

¹H-NMR(DMSO-d₆): δ 6.96(1H, d, J=9.0 Hz), 7.12-7.18(1H, m),7.35-7.41(2H, m), 7.58(1H, dd, J=8.7, 2.7 Hz), 7.67-7.71(2H, m),8.08(1H, d, J=2.7 Hz), 10.43(1H, s), 11.87(1H, s).

Example 140 Preparation of the Compound of Compound No. 140

Using 5-bromosalicylic acid and 3-chloroaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 63.1%.

mp 231-232° C.

¹H-NMR(DMSO-d₆): δ 6.97(1H, d, J=8.7 Hz), 7.19-7.22(1H, m),7.38-7.43(1H, m), 7.57-7.63(2H, m), 7.91-7.92(1H, m), 8.01(1H, d, J=2.7Hz), 10.49(1H, s), 11.64(1H, s).

Example 141 The Compound of Compound No. 141

This compound is a commercially available compound.

-   Supplier: Tokyo Kasei.-   Catalog code number: B0897.

Example 142 Preparation of the Compound of Compound No. 142

Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 10.8%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.24-7.28(1H, m),7.50-7.54(1H, m), 7.61(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=2.7 Hz),8.58(1H, d, J=2.4 Hz), 11.02(1H, s), 12.35(1H, brs).

Example 143 Preparation of the Compound of Compound No. 143

Using 5-bromosalicylic acid and 3,4-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 58.2%.

mp 249-251° C.

¹H-NMR(DMSO-d₆): δ 6.97(1H, d, J=8.7 Hz), 7.57-7.70(3H, m), 7.98(1H, d,J=2.7 Hz), 8.10(1H, d, J=2.4 Hz), 10.54(1H, s), 11.55(1H, s).

Example 144 Preparation of the Compound of Compound No. 144

Using 5-bromosalicylic acid and 3,5-difluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 36.3%.

mp 259-261° C.

¹H-NMR(DMSO-d₆): δ 6.96-7.04(2H, m), 7.45-7.54(2H, m), 7.58(1H, dd,J=8.7, 2.7Hz), 7.94(1H, d, J=2.7 Hz), 10.60(1H, s) 11.48(1H, s).

Example 145 Preparation of the Compound of Compound No. 172

Using O-acetylsalicyloyl chloride and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 2(1) gave the titlecompound.

Yield: 73.5%.

mp 167-168° C.

¹H-NMR(CDCl₃): δ 2.35(3H, s), 7.14-7.18(2H, m), 7.35-7.40(1H, m),7.52-7.57(3H, m), 7.81(1H, dd, J=7.8, 1.8 Hz), 8.05(1H, brs).

Example 146 Preparation of the Compound of Compound No. 145

Using 2-acetoxy-N-(3,5-dichlorophenyl)benzamide (Compound No. 172) asthe raw material, the same operation as the Example 2(2) gave the titlecompound.

Yield: 60.3%.

mp 218-219° C.

¹H-NMR(DMSO-d₆): δ 6.95-7.02(2H, m), 7.35-7.36(1H, m), 7.42-7.47(1H, m),7.83-7.87(3H, m), 10.54(1H, s), 11.35(1H, s).

Example 147 Preparation of the Compound of Compound No. 146

Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 33.3%.

mp 258-260° C.

¹H-NMR(DMSO-d₆): δ 7.00-7.05(1H, m), 7.28-7.37(2H, m), 7.63(1H, dd,J=9.3, 3.3Hz), 7.84(2H, d, J=2.1 Hz), 10.56(1H, s), 11.23(1H, s).

Example 148 Preparation of the Compound of Compound No. 147

Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 41.2%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.0 Hz), 7.36-7.37(1H, m), 7.48(1H, dd,J=8.7, 2.7 Hz), 7.83-7.84(3H, m), 10.56(1H, s), 11.44(1H, s).

Example 149 Preparation of the Compound of Compound No. 148

Using 5-bromosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 61.6%.

mp 243-244° C.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.36-7.37(1H, m), 7.59(1H, dd,J=9.0, 2.4 Hz), 7.83(2H, d, J=1.8 Hz), 7.95(1H, d, J=2.4 Hz), 10.56(1H,s), 11.46(1H, s).

Example 150 Preparation of the Compound of Compound No. 149

Using 5-iodosalicylic acid and 3,5-dichloroaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 65.4%.

mp 244-245° C.

¹H-NMR(DMSO-d₆): δ 6.84(1H, d, J=9.0 Hz), 7.35-7.37(1H, m), 7.72(1H, dd,J=9.0, 2.1 Hz), 7.83(2H, d, J=1.8 Hz), 8.09(1H, d, J=2.1 Hz), 10.55(1H,s), 11.45(1H, s).

Example 151 Preparation of the Compound of Compound No. 150

Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 44.2%.

mp 181-182° C.

¹H-NMR(DMSO-d₆): δ 7.42-7.43(1H, m), 7.80(2H, d, J=1.8 Hz), 8.03(1H, d,J=2.1 Hz), 8.17(1H, d, J=2.1 Hz), 10.82(1H, s).

Example 152 Preparation of the Compound of Compound No. 151

Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 57.2%.

mp 255-256° C.

¹H-NMR(DMSO-d₆): δ 7.03-7.06(2H, m), 7.34-7.36(1H, m), 7.82-7.85(3H,m),10.51(1H, s), 11.70(1H, brs).

Example 153 Preparation of the Compound of Compound No. 152

Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 83.1%.

mp 232-233° C.

¹H-NMR(DMSO-d₆): δ 7.16(1H, d, J=9.6 Hz), 7.37-7.39(1H, m), 7.84(1H, d,J=2.1 Hz), 8.29(1H, dd, J=9.0, 3.0 Hz), 8.65(1H, d, J=3.0 Hz), 10.83(1H,s).

Example 154 Preparation of the Compound of Compound No. 153

Using 5-methylsalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 71.0%.

mp 216-217° C.

¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 6.90(1H, d, J=8.4 Hz), 7.26(1H, dd,J=8.7, 1.8 Hz), 7.34-7.36(1H, m), 7.67(1H, d, J=1.5 Hz), 7.85(2H, d,J=1.8 Hz), 10.52(1H, s), 11.15(1H, s).

Example 155 Preparation of the Compound of Compound No. 154

Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 29.8%.

mp 230-232° C.

¹H-NMR(DMSO-d₆): δ 3.76(3H, s), 6.95(1H, d, J=8.7 Hz), 7.08(1H, dd,J=9.0, 3.0 Hz), 7.35-7.36(1H, m), 7.40(1H, d, J=3.0 Hz), 7.85(2H, d,J=1.5 Hz), 10.55(1H, s), 10.95(1H, s).

Example 156 Preparation of the Compound of Compound No. 155

Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 78.6%.

mp 297-299° C.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=9.0 Hz), 7.58(1H, dd, J=8.4, 2.4 Hz),7.95(1H, d, J=2.4 Hz), 8.03(1H, s), 10.58(1H, s), 11.49(1H, s).

Example 157 Preparation of the Compound of Compound No. 156

Using 5-bromosalicylic acid and 3,5-dichloro-4-hydroxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 22.5%.

¹H-NMR(DMSO-d₆): δ 6.96(1H, d, J=8.7 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz),7.76(2H, s), 8.01(1H, d, J=2.4 Hz), 10.03(1H, s), 10.36(1H, s),11.67(1H, brs).

Example 158 Preparation of the Compound of Compound No. 157

Using 5-chlorosalicylic acid and 2,3,4,5,6-pentafluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 58.6%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.91(1H, d, J=2.7 Hz), 10.38(1H, brs), 11.74(1H, brs).

Example 159 Preparation of the Compound of Compound No. 158

Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 32.2%.

mp 258-260° C.

¹H-NMR(DMSO-d₆): δ 6.98-7.02(1H, m), 7.59-7.63(1H, m), 7.96-7.97(1H, m),8.56-8.58(1H, m), 9.03-9.05(2H, m), 11.04(1H, s), 11.39(1H, brs).

Example 160 Preparation of the Compound of Compound No. 159

Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 75.7%.

¹H-NMR(DMSO-d₆): δ 1.27(9H, s), 1.33(9H, s), 7.04(1H, d, J=9.0 Hz),7.26(1H, dd, J=8.4, 2.1 Hz), 7.35-7.38(2H, m), 7.49(1H, dd, J=8.7, 2.7Hz), 8.07(1H, d, J=2.4 Hz), 10.22(1H, s), 12.38(1H, br s).

Example 161 Preparation of the Compound of Compound No. 160

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 89.5%.

¹H-NMR(DMSO-d₆): δ 1.28(9H, s), 3.33(3H, s), 7.01(1H, d, J=8.7 Hz),7.05(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, dd, J=9.0,3.0 Hz), 7.99(1H, d, J=3.0 Hz), 8.49(1H, d, J=2.4 Hz), 10.78(1H, s),12.03(1H, s).

Example 162 Preparation of the Compound of Compound No. 161

Using 5-bromosalicylic acid and 3,5-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 58.1%.

mp 188-190° C.

¹H-NMR(DMSO-d₆): δ 2.28(6H, s), 6.80(1H, s), 6.96(1H, d, J=8.7 Hz),7.33(2H, s), 7.58(1H, dd, J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4 Hz),10.29(1H, s), 11.93(1H, brs).

Example 163 Preparation of the Compound of Compound No. 162

Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 34.1%.

¹H-NMR(CDCl₃): δ 1.26(18H, s), 6.99(1H, d, J=8.7 Hz), 7.29(1H, t, J=1.8Hz), 7.39(1 dd, J=9.0, 2.4 Hz), 7.41(2H, d, J=1.5 Hz), 7.51(1H, d, J=2.1Hz), 7.81(1H, br s), 12.01(1H, s).

Example 164 Preparation of the Compound of Compound No. 163

Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 45.2%.

¹H-NMR(DMSO-d₆): δ 1.30(18H, s), 6.95(1H, d, J=8.7 Hz), 7.20(1H, t,J=1.5 Hz), 7.56(2H, d, J=1.5 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 8.12(1H,d, J=2.7 Hz), 10.39(1H, s), 11.98(1H, s).

Example 165 Preparation of the Compound of Compound No. 164

Using 5-chlorosalicylic acid and2-amino-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 77.5%.

¹H-NMR(DMSO-d₆): δ 1.23(6H, s), 1.24(6H, s), 1.64(4H, s), 2.19(3H, s),7.13(1H, d, J=9.0 Hz), 7.20(1H, s), 7.49(1H, dd, J=8.7, 2.7 Hz),7.67(1H, s), 8.04(1H, d, J=2.7 Hz), 10.23(1H, s), 12.26(1H, s).

Example 166 Preparation of the Compound of Compound No. 165

Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 75.6%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.35-7.44(1H, m),7.45-7.54(5H, m), 7.65-7.68(2H, m), 7.72(1H, dt, J=7.2, 2.1 Hz).7.99(1H,d, J=3.0 Hz), 8.03(1H, m), 10.50(1H, s), 11.83(1H, brs).

Example 167 Preparation of the Compound of Compound No. 166

Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 37.0%.

¹H-NMR(DMSO-d₆): δ 3.95(3H, s), 7.08(1H, d, J=8.7 Hz), 7.20(1H, d, J=8.4Hz), 7.34(1H, t, J=7.2 Hz), 7.40-7.50(4H, m), 7.62(1H, d, J=8.7 Hz),8.00(1H, d, J=3.0 Hz), 8.77(1H, d, J=2.1 Hz), 10.92(1H, s), 12.09(1H,s).

Example 168 Preparation of the Compound of Compound No. 167

Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 39.7%.

¹H-NMR(DMSO-d₆): δ 3.72(3H, s), 3.84(3H, s), 6.66(1H, ddd, J=9.0, 3.0,0.6 Hz), 6.99-7.03(2H, m), 7.58(1H, ddd, J=9.0, 2.7, 0.6 Hz), 8.10(1H,dd, J=2.4, 0.6 Hz), 8.12(1H, d, J=3.0 Hz), 10.87(1H, s), 12.08(1H, s).

Example 169 Preparation of the Compound of Compound No. 168

Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 40.3%.

mp 207-209° C.

¹H-NMR(DMSO-d₆): δ 3.75(6H, s), 6.30-6.32(1H, m), 6.94-6.97(3H, m),7.57(1H, dd, J=8.7, 2.4 Hz), 8.04(1H, d, J=2.4 Hz), 10.32(1H, s),11.78(1H, s).

Example 170 Preparation of the Compound of Compound No. 169

Using 5-chlorosalicylic acid and 3-acetylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 80.0%.

¹H-NMR(DMSO-d₆): δ 2.60(3H, s), 7.03(1H, d, J=9.0 Hz), 7.49(1H, dd,J=9.0, 3.0 Hz), 7.54(1H, t, J=8.1 Hz), 7.76(1H, dq, J=7.8, 0.9 Hz),7.96-8.00(2H, m), 8.30(1H, t, J=1.8 Hz), 10.56(1H, s), 11.75(1H, s).

Example 171 Preparation of the Compound of Compound No. 170

Using 5-bromosalicylic acid and 5-aminoisophthalic acid dimethyl esteras the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 74.1%.

mp 254-256° C.

¹H-NMR(DMSO-d₆): δ 3.92(6H, s), 6.97(1H, d, J=9.0 Hz), 7.60(1H, dd,J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 8.24-8.25(1H, m), 8.62(2H, m),10.71(1H, s), 11.57(1H, s).

Example 172 The Compound of Compound No. 171

This compound is a commercially available compound.

-   Supplier: Maybridge.-   Catalog code number: RDR 01434

Example 173 Preparation of the Compound of Compound No. 173

Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 61.1%.

¹H-NMR(DMSO-d₆): δ 1.27(9H, s), 1.33(9H, s), 2.28(3H, s), 6.89(1H, d,J=8.1 Hz), 7.24(1H, d, J=2.1 Hz), 7.27(1H, d, J=2.1 Hz), 7.32(1H, d,J=2.4 Hz), 7.37(1H, d, J=8.4 Hz), 7.88(1H, d, J=1.5 Hz), 10.15(1H, s),11.98(1H, br s).

Example 174 Preparation of the Compound of Compound No. 174

Using N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide(Compound No. 162) and acetyl chloride as the raw materials, the sameoperation as the Example 96 gave the title compound.

Yield: 66.1%.

¹H-NMR(CDCl₃): δ 1.34(18H, s), 2.36(3H, s), 7.12(1H, d, J=8.4Hz),7.25(1H, d, J=1.5 Hz), 7.44(2H, d, J=1.2 Hz), 7.47(1H, dd, J=8.7,2.7 Hz), 7.87(1H, d, J=2.4 Hz), 7.98(1H, s).

Example 175 Preparation of the Compound of Compound No. 175

Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 46.7%.

¹H-NMR(CDCl₃): δ 1.37(18H, s), 7.13(1H, d, J=9.3 Hz), 7.32(1H, t, J=1.8Hz), 7.46(2H, d, J=1.8 Hz), 8.07(1H, s), 8.33(1H, dd, J=9.3, 2.1 Hz),8.59(1H, d, J=2.4 Hz), 13.14(1H, s).

Example 176 Preparation of the Compound of Compound No. 176

Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 16.3%.

¹H-NMR(CDCl₃): δ 1.35(18H, s), 2.35(3H, s), 6.94(1H, d, H=8.4 Hz),7.23-7.28(2H, m), 7.31(1H, s), 7.42(1H, d, J=1.8 Hz), 7.88(1H, s),11.86(1H, s).

Example 177 Preparation of the Compound of Compound No. 177

Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 12.7%.

¹H-NMR(DMSO-d₆): δ 1.30(18H, s), 3.77(3H, s), 6.91(1H, d, J=9.0 Hz),7.07(1H, dd, J=8.7, 3.0 Hz), 7.19-7.20(1H, m), 7.52-7.54(3H, m),10.33(1H, s), 11.44(1H, s).

Example 178 Preparation of the Compound of Compound No. 178

Using5-chloro-N-{5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl}-2-hydroxybenzamide(Compound No. 160) and acetyl chloride as the raw materials, the sameoperation as the Example 96 gave the title compound.

Yield: 87.5%.

¹H-NMR(CDCl₃): δ 1.35(9H, s), 2.37(3H, s), 3.91(3H, s), 6.86(1H, d,J=8.7 Hz),7.12(1H, dd, J=8.7, 2.4 Hz), 7.13(1H, d, J=9.0 Hz), 7.47(1H,dd, J=9.0, 2.4 Hz), 8.02(1H, d, J=2.7 Hz), 8.66(1H, d, J=2.4 Hz),8.93(1H, s).

Example 179 Preparation of the Compound of Compound No. 179

Using 5-methylsalicylic acid and5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 84.7%.

¹H-NMR(CDCl₃): δ 1.35(9H, s), 2.34(3H, s), 3.93(3H, s), 6.86(1H, d,J=8.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz), 7.24(1H,dd, J=8.4, 1.8 Hz), 7.27(1H, br s), 8.48(1H, d, J=2.4 Hz), 8.61(1H,brs), 11.95(1H, s).

Example 180 Preparation of the Compound of Compound No. 179

Using 5-bromosalicylic acid and 2-aminothiazole as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 12.0%.

mp 212° C. (dec.).

¹H-NMR(DMSO-d₆): δ 6.94(1H, brd, J=8.0 Hz), 7.25(1H, brd, J=3.2 Hz),7.56(2H, m), 8.05(1H, d, J=2.8 Hz).

Example 181 Preparation of the Compound of Compound No. 186 (1)2-Amino-4-[(1,1-dimethyl)ethyl]thiazole

A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol),thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5hours. After cooling, the reaction mixture was poured into saturatedaqueous sodium hydrogen carbonate and extracted with ethyl acetate.After the organic layer was washed with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was purified by chromatography on silicagel(n-hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g,90.9%) as an yellowish white powder.

¹H-NMR(CDCl₃): δ 1.26(9H, s), 4.96(2H, brs), 6.09(1H, s).

When the method described in Example 181(1) is referred in the followingexamples, solvents such as ethanol or the like were used as the reactionsolvent.

(2) 2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide

Using 2-acetoxy-5-bromobenzoic acid and2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the sameoperation as the Example 24 gave the title compound.

Yield: 59.4%.

¹H-NMR(CDCl₃): δ 1.31(9H, s), 2.44(3H, s), 6.60(1H, s), 7.13(1H, d,J=8.4 Hz), 7.68(1H, dd, J=8.7, 2.4 Hz), 8.17(1H, d, J=2.4 Hz), 9.72(1H,brs).

(3) 5-Bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 186)

2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide(100.1 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL). 2N Sodiumhydroxide (0.2 ml) was added, and the mixture was stirred at roomtemperature for 20 minutes. The reaction mixture was poured into dilutedhydrochloric acid and extracted with ethyl acetate. After the organiclayer was washed with brine, dried over anhydrous sodium sulfate, theresidue obtained by evaporation under reduced pressure was crystallized(isopropyl ether/n-hexane) to give the title compound (70.1 mg, 78.9%)as a white powder.

¹H-NMR(DMSO-d₆): δ 1.30(9H, s), 6.80(1H, brs), 6.95(1H, brs), 7.57(1H,brs), 8.06(1H, d, J=2.4 Hz), 11.82(1H, brs), 13.27(1H, brs).

Example 182 Preparation of the Compound of Compound No. 181 (1)2-Acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide

2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide(compound of Example 181(2); 0.20 g, 0.50 mmol) was dissolved inacetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.55 mmol) was added,and the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by chromatography on silica gel(n-hexane:ethylacetate=3:1) to give the title compound as a crude product.

(2)5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 181)

Using2-acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamideas the raw material, the same operation as the Example 2(2) gave thetitle compound.

Yield: 90.9% (2 steps).

¹H-NMR(DMSO-d₆): δ 1.42(9H, s), 6.99(1H, d, J=8.7 Hz), 7.61(1H, dd,J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.79(1H, brs), 12.00(1H, brs).

Example 183 Preparation of the Compound of Compound No. 182

Using 5-bromosalicylic acid and2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 22.4%.

mp 215° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.8 Hz), 7.61(1H, dd, J=8.8, 2.8 Hz),7.97(1H, d, J=2.4 Hz).

[2-Amino-5-bromo-4-(trifluoromethyl)thiazole: Refer to “Journal ofHeterocyclic Chemistry”, (USA), 1991, Vol. 28, p. 1017.]

Example 184 Preparation of the Compound of Compound No. 183 (1)α-Bromo-pivaloylacetonitrile

Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbontetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added,and the mixture was refluxed for 15 minutes. After cooling, theinsoluble matter was filtered off, and the residue obtained byevaporation of the filtrate under reduced pressure was purified bychromatography on silica gel(n-hexane:ethyl acetate=4:1) to give thetitle compound (1.43 g, 87.9%) as an yellowish brown oil.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 5.10(1H, s).

When the method described in Example 184(1) is referred in the followingexamples, N-bromosuccinimide was used as the brominating agent. As thereaction solvent, solvents such as carbon tetrachloride or the like wereused.

(2) 2-Amino-5-cyano-4-[(1,1-dimethyl)ethyl]thiazole

Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials,the same operation as the Example 181(1) gave the title compound.

Yield: 66.3%.

¹H-NMR(CDCl₃): δ 1.41(9H, s), 5.32(2H, s).

(3)5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 183)

Using 5-chlorosalicylic acid and2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 63.4%.

¹H-NMR(DMSO-d₆): δ 1.43(9H, s), 7.06(1H, d, J=8.7 Hz), 7.51(1H, dd,J=8.7, 3.0 Hz), 7.85(1H, d, J=2.7 Hz), 12.31(2H, br).

Example 185 Preparation of the Compound of Compound No. 184

Using 5-bromosalicylic acid and2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole (compound of Example184(2)) as the raw materials, the same operation as the Example 16 gavethe title compound.

Yield: 61.3%.

¹H-NMR(DMSO-d₆): δ 1.43(9H, s), 7.00(1H, d, J=8.7 Hz), 7.62(1H, dd,J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz), 11.75(1H, br), 12.43(1H, br).

Example 186 Preparation of the Compound of Compound No. 185

Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 12.9%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 6.91(1H, d, J=7.6 Hz), 7.26(1H, s),7.54(1H, d, J=9.6 Hz), 8.03(1H, d, J=2.8 Hz).

Example 187 Preparation of the Compound of Compound No. 187

Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 14.4%.

¹H-NMR(DMSO-d₆): δ 2.18(3H, s), 2.22(3H, s), 6.89(1H, d, J=8.8 Hz),7.51(1H, d, J=6.8 Hz), 8.02(1H, d, J=2.8 Hz), 13.23(1H, brs).

Example 188 Preparation of the Compound of Compound No. 188

Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 27.7%.

mp 243-244° C.

¹H-NMR(CD₃OD): δ 2.47(3H, s), 6.92(1H, d, J=8.7 Hz), 7.36-7.41(1H, m),7.44-7.50(2H, m), 7.53(1H, dd, J=9.0, 2.7 Hz), 7.57-7.61(2H, m),8.16(1H, d, J=2.7 Hz).

[2-Amino-5-methyl-4-phenylthiazole: Refer to “Yakugaku Zasshi: Journalof The Pharmaceutical Society of Japan”, 1961, Vol. 81, p. 1456.]

Example 189 Preparation of the Compound of Compound No. 189

Using (4-fluorophenyl)acetone as the raw material, the same operation asthe Examples 184(1)-(3) gave the title compound.

Yield: 28.8% (3 steps).

(1) α-Bromo-(4-fluorophenyl)acetone

¹H-NMR(CDCl₃): δ 2.33(3H, s), 5.41(1H, s), 7.07(2H, t, J=8.7 Hz),7.43(2H, dd, J=8.7, 5.1 Hz).

(2) 2-Amino-4-methyl-5-(4-fluorophenyl)thiazole

¹H-NMR(CDCl₃): δ 2.27(3H, s), 4.88(2H, s), 7.07(2H, t, J=8.7 Hz),7.32(2H, dd, J=8.7, 5.4 Hz).

(3)5-Bromo-N-[4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide(Compound No. 189)

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 6.95(1H, d, J=8.4 Hz), 7.33(2H, t, J=8.7Hz), 7.52-7.59(3H, m), 8.06(1H, d, J=3.0 Hz), 12.01-13.65(2H, br).

Example 190 Preparation of the Compound of Compound No. 190

Using 3-(trifluoromethyl)phenylacetone as the raw material, the sameoperation as the Examples 184(1)-(3) gave the title compound.

Yield: 39.8% (3 steps).

(1) α-Bromo-3-(trifluoromethyl)phenylacetone

¹H-NMR(CDCl₃): δ 2.38(3H, s), 5.43(1H, s), 7.52(1H, t, J=7.8 Hz),7.61-7.66(2H, m), 7.69-7.70(1H, m).

(2) 2-Amino-4-methyl-5-[3-(trifluoromethyl)phenyl]thiazole

¹H-NMR(CDCl₃): δ 2.32(3H, s), 4.95(2H, s), 7.46-7.56(3H, m),7.59-7.61(1H, m).

(3)5-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl}-2-hydroxy-benzamide(Compound No. 190)

¹H-NMR(DMSO-d₆): δ 2.40(3H, s), 6.97(1H, d, J=8.7 Hz), 7.59(1H, dd,J=8.7, 2.4 Hz), 7.71-7.84(4H, m), (2H, m), 8.06(1H, d, J=2.4 Hz),12.09(1H, br), 12.91-13.63(1H, br).

Example 191 Preparation of the Compound of Compound No. 191

Using 2,2-dimethyl-3-hexanone as the raw material, the same operation asthe Examples 184(1)-(3) gave the title compound.

Yield: 17.0% (3 steps).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-ethylthiazole

¹H-NMR(CDCl₃): δ 1.21(3H, t, J=7.5 Hz), 1.32(9H, s), 2.79(2H, q, J=7.5Hz), 4.63(2H, brs).

(3)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl}-2-hydroxybenzamide(Compound No. 191)

¹H-NMR(CDCl₃): δ 1.32(3H, t, J=7.5 Hz), 1.41(9H, s), 2.88(2H, q, J=7.5Hz), 6.84(1H, d, J=9.0 Hz), 7.44(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d,J=2.7 Hz), 11.46(2H, br).

Example 192 Preparation of the Compound of Compound No. 192

Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 17.4%.

mp 224-225° C.

¹H-NMR(DMSO-d₆): δ 1.24(3H, t, J=7.6 Hz), 2.70(2H, q, J=7.6 Hz),6.95(1H, brd, J=7.6 Hz), 7.39-7.42(1H, m), 7.45-7.51(4H, m), 7.56(1H,brd, J=8.0 Hz), 8.06(1H, d, J=2.8 Hz), 11.98(1H, brs).

Example 193 Preparation of the Compound of Compound No. 193

Using benzyl isopropyl ketone as the raw material, the same operation asthe Examples 184(1)-(3) gave the title compound.

Yield: 4.4% (3 steps).

(2) 2-Amino-4-isopropyl-5-phenylthiazole

¹H-NMR(CDCl₃): δ 1.23(6H, d, J=6.6 Hz), 3.05(1H, m), 4.94(2H, s),7.28-7.41(5H, m).

(3) 5-Bromo-N-(4-isopropyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 193)

¹H-NMR(DMSO-d₆): δ 1.26(6H, d, J=6.0 Hz), 3.15(1H, m), 6.98(1H, brs),7.43-7.53(5H, m), 7.59(1H, brs), 8.08(1H, d, J=2.7 Hz), 11.90(1H, brd),13.33(1H, brd).

Example 194 Preparation of the Compound of Compound No. 194

Using 1-phenyl-2-hexanone as the raw material, the same operation as theExamples 184(1)-(3) gave the title compound.

Yield: 52.6% (3 steps).

(1) α-Bromo-1-phenyl-2-hexanone

¹H-NMR(CDCl₃):δ 0.85(3H, t, J=7.2 Hz), 1.19-1.32(2H, m), 1, 50-1.60(2H,m), 2.59(2H, td, J=7.5, 3.9 Hz), 5.44(1H, s), 7.34-7.45(5H, m).

(2) 2-Amino-4-butyl-5-phenylthiazole

¹H-NMR(CDCl₃): δ 0.89(3H, t, J=7.5 Hz), 1.28-1.41(2H, m), 1.61-1.71(2H,m), 2.56-2.61(2H, m), 4.87(2H, s), 7.25-7.40(5H, m).

(3) 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 194)

¹H-NMR(DMSO-d₆): δ 0.85(3H, t, J=7.2 Hz), 1.23-1.35(2H, m),1.59-1.69(2H, m), 2.70(2H, t, J=7.2 Hz), 6.96(1H, d, J=6.9 Hz),7.39-7.59(6H, m), 8.07(1H, d, J=2.4 Hz), 11.93(1H, br), 13.18-13.59(1H,br).

Example 195 Preparation of the Compound of Compound No. 195 (1)4-Bromo-2,2,6,6-tetramethyl-3,5-heptanedione[α-Bromo-dipivaloylmethane]

2,2,6,6-Tetramethyl-3,5-heptanedione(dipivaloylmethane; 1.00 g, 5.42mmol) was dissolved in carbon tetrachloride (10 mL). N-Bromosuccinimide(965.8 mg, 5.42 mmol) was added, and the mixture was refluxed for 2hours. After cooling, the insoluble matter was filtered off, and thefiltrate was evaporated under reduced pressure to give the titlecompound (1.42 g, quant.) as a white crystal.

¹H-NMR(CDCl₃): δ 1.27(18H, s), 5.67(1H, s).

When the method described in Example 195(1) is referred in the followingexamples, N-bromosuccinimide was used as the brominating agent. As thereaction solvent, solvents such as carbon tetrachloride or the like wereused.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl)-5-[(2,2-dimethyl)propionyl]thiazole

A mixture of4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione(α-bromo-dipivaloylmethane;1.42 g, 5.40 mmol), thiourea (451.8 mg, 5.94 mmol) and ethanol (15 mL)was refluxed for 2 hours. After cooling, the reaction mixture was pouredinto saturated aqueous sodium hydrogen carbonate and extracted withethyl acetate. After the organic layer was washed with water and brine,dried over anhydrous sodium sulfate, the residue obtained by evaporationunder reduced pressure was crystallized (dichloromethane/hexane) to givethe title compound (1.23 g, 94.5%) as a white crystal.

¹H-NMR(CDCl₃): δ 1.26(9H, s), 1.29(9H, s), 5.03(2H, s).

(3)5-Chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide(Compound No. 195)

A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol),2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole(200.0 mg, 0.83 mmol), phophorus trichloride (40 μl, 0.46 mmol) andchlorobenzene (4 mL) was refluxed for 3 hours. The residue obtained byconcentration of the reaction mixture under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=3:1) togive the title compound (159.1 mg, 48.4%) as a white powder.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 1.35(9H, s), 6.99(1H, d, J=8.7 Hz),7.43(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d, J=2.7 Hz), 10.52(2H, br).

When the method described in Example 195(3) is referred in the followingexamples, phophorus trichloride was used as the acid halogenating agent.As the reaction solvent, solvents such as monochlorobenzene, toluene orthe like were used.

Example 196 Preparation of the Compound of Compound No. 196

Using 5-bromosalicylic acid and2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole(compound of Example 195(2)) as the raw materials, the same operation asthe Example 195(3) gave the title compound.

Yield: 23.8%.

¹H-NMR(CDCl₃): δ 1.33(9H, s), 1.35(9H, s), 6.94(1H, d, J=8, 7 Hz),7.55(1H, dd, J=8.7, 2.1 Hz), 7.85(1H, d, J=2.1 Hz), 10.51(2H, br).

Example 197 Preparation of the Compound of Compound No. 197

Using pivaloylacetic acid ethyl ester as the raw material, the sameoperation as the Examples 195(1)-(3) gave the title compound.

Yield: 45.7% (3 steps).

(1) α-Bromo-pivaloylacetic acid ethyl ester

¹H-NMR(CDCl₃): δ 1.28(9H, s), 1.29(3H, t, J=7.2 Hz), 4.26(2H, q, J=7.2Hz), 5.24(1H, s).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethylester

¹H-NMR(CDCl₃): δ 1.32(3H, t, J=7.2 Hz), 1.43(9H, s), 4.24(2H, q, J=7.2Hz), 5.18(2H, s).

(3)2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylicacid ethyl ester (Compound No. 197)

¹H-NMR(DMSO-d₆): δ 1.30(3H, t, J=7.2 Hz), 1.44(9H, s), 4.27(2H, q, J=6.9Hz), 7.00(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 8.02(1H, d,J=2.4 Hz), 11.80(1H, br), 12.12(1H, br).

Example 198 Preparation of the Compound of Compound No. 198 (1)2-Amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole

2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 181(1);0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9 mL).N-Bromosuccinimide (1.00 g, 5.6 mmol) was added, and the mixture wasstirred at room temperature for 1 hour. Hexane was added to the reactionmixture. The insoluble matter was filtered off, and the residue obtainedby evaporation of the filtrate under reduced pressure was purified bychromatography on silica gel(hexane:ethyl acetate=2:1) to give the titlecompound (1.23 g, 93.7%) as an yellowish gray powder.

¹H-NMR(CDCl₃): δ 1.39(9H, s), 4.81(2H, brs).

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole

A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g,0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) andacetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture waspoured into water and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=2:1) togive the title compound (80.7 mg, 79.3%) as an yellow crystal.

¹H-NMR(CDCl₃): δ 1.32(9H, s), 1.64(4H, t, J=5.7 Hz), 1.71-1.77(2H, m),2.35(2H, brs), 2.99(2H, brs), 4.68(2H, s).

When the preparation method described in Example 198(2) is referred inthe following examples, bases such as potassium carbonate or the likewere used as the base. As the reaction solvent, solvents such asacetonitrile or the like were used.

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl)-5-piperidinothiazol-2-yl}benzamide

Under argon atmosphere, phosphorus oxychloride (46 μl, 0.50 mmol) wasadded to a mixture of 2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg,0.34 mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL), and themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into 2N hydrochloric acid and extracted with ethylacetate. After the organic layer was washed with water and brine, driedover anhydrous sodium sulfate, the residue obtained by evaporation underreduced pressure was purified by chromatography on silicagel(n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) asa crude product.

When the preparation method described in Example 198(3) is referred inthe following examples, phosphorus oxychloride was used as the acidhalogenating agent. As the reaction base, pyridine was used. As thereaction solvent, solvents such as dichloromethane, tetrahydrofuran orthe like were used.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-2-hydroxybenzamide(Compound No. 198)

2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-benzamide(crude product, 84.3 mg) was dissolved in ethanol (3 mL). 2N Aqueoussodium hydroxide (0.1 mL) was added, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation under reduced pressure waspurified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) togive the title compound (54.1 mg, 36.3%; 2 steps) as a white powder.

¹H-NMR(CDCl₃): δ 1.41(9H, s), 1.56(2H, brs), 1.67-1.74(4H, m), 2.79(4H,brs), 6.85(1H, d, J=9.0 Hz), 7.45(1H, dd, J=9.0, 2.4 Hz), 8.06(1H, d,J=2.4 Hz), 11.70(2H, br).

When the preparation method described in Example 198(4) is referred inthe following examples, inorganic bases such as sodium hydroxide,potassium carbonate or the like were used as the base. As the reactionsolvent, solvents such as water, methanol, ethanol, tetrahydrofuran orthe like were used alone or as a mixture.

Example 199 Preparation of the Compound of Compound No. 199

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 198(1)) and morpholine as the raw materials, the same operationas the Examples 198(2)-(4) gave the title compound.

Yield: 17.1%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-morpholinothiazole

¹H-NMR(CDCl₃): δ 1.33(9H, s), 2.76(4H,brs), 3.79(4H, brs), 4.66(2H, s).

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}-2-hydroxybenzamide(Compound No. 199)

¹H-NMR(CDCl₃): δ 1.24(9H, s), 2.89(4H, dd, J=4.8, 4.2 Hz), 3.83(4H, dd,J=4.5, 4.2 Hz), 6.89(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.4 Hz),7.98(1H, d, J=2.1 Hz), 11.20(2H, br).

Example 200 Preparation of the Compound of Compound No. 200

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 198(1)) and 4-methylpiperazine as the raw materials, the sameoperation as the Examples 198(2)-(4) gave the title compound.

Yield: 6.9%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazole

¹H-NMR(DMSO-d₆): δ 1.25(9H, s), 2.12(2H, brs), 2.19(3H, s), 2.57(2H,brs), 2.72(4H, brs), 6.51(2H, s).

(3)2-Acetoxy-N-{4-[(1,1-dimethyl)ethyl)-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide(Compound No. 200)

¹H-NMR(CD₃OD): δ 1.41(9H, s), 2.55(3H, s), 2.87(4H, brs), 3.03(4H, brs),6.88(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz), 8.11(1H, d, J=2.7Hz).

Example 201 Preparation of the Compound of Compound No. 201

Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (compound ofExample 198(1)) and 4-phenylpiperazine as the raw materials, the sameoperation as the Examples 198(2)-(4) gave the title compound.

Yield: 6.9%.

(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazole

¹H-NMR(CDCl₃): δ 1.34(9H, s), 2.80(2H, brs), 3.03(4H, brs), 3.55(2H,brs), 4.69(2H, s), 6.88(1H, tt, J=7.2, 1.2 Hz), 6.95(2H, dd, J=9.0, 1.2Hz), 7.28(2H, dd, J=8.7, 7.2 Hz).

(3)2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl}thiazol-2-yl)benzamide

The product was used for the next reaction as a crude product.

(4)5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl}-2-hydroxybenzamide(Compound No. 201)

¹H-NMR(DMSO-d₆): δ 1.39(9H, s), 2.97(4H, s), 3.30(4H, s), 6.82(1H, t,J=7.5 Hz), 6.97(2H, brs), 6.99(2H, t, J=7.5 Hz), 7.58(1H, brs), 8.05(1H,d, J=2.4 Hz), 11.69(1H, brs), 11.82(1H, brs).

Example 202 Preparation of the Compound of Compound No. 202

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 16.0%.

mp 239° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.6 Hz),7.44(2H, t, J=7.6 Hz), 7.62(1H, dd, J=8.4, 2.8 Hz), 7.67(1H, s),7.92(2H, d, J=7.2 Hz), 8.08(1H, d, J=2.8 Hz), 11.88(1H, brs), 12.05(1H,brs).

Example 203 Preparation of the Compound of Compound No. 203 (1){2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acidmethyl ester

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acidmethyl ester as the raw materials, the same operation as the Example195(3) gave the title compound.

Yield: 32.1%.

mp 288.5-229.5° C.

¹H-NMR(DMSO-d₆): δ 3.66(3H, s), 3.95(2H, s), 6.99(1H, d, J=8.0 Hz),7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6 Hz), 7.56-7.61(3H, m),8.07(1H, d, J=2.4 Hz), 11.85(1H, brs), 11.98(1H, brs).

(2) {2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}aceticacid (Compound No. 203)

{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acidmethyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5 mL). 2NSodium hydroxide (0.5 mL, 1 mmol) was added, and the mixture was stirredat room temperature for 12 hours. The reaction mixture was poured into2N hydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The obtained residue was suspended and washed withn-hexane-ethyl acetate under heating at reflux to give the titlecompound (56 mg, 77.3%) as a light yellow white crystal.

mp 284-286° C.

¹H-NMR(DMSO-d₆): δ 3.84(2H, s), 6.98(1H, d, J=8.8 Hz), 7.42(1H, d, J=6.8Hz), 7.49(2H, t, J=7.6 Hz), 7.58-7.61(3H, m), 8.07(1H, d, J=2.8 Hz),12.25(H, brs).

Example 204 Preparation of the Compound of Compound No. 204

Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 25.9%.

mp 262-263° C.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.1 Hz), 7.34-7.47(10H, m), 7.63(1H, d,J=6.9 Hz), 8.08(1H, d, J=2.4 Hz), 11.88(1H, brs), 12.08(1H, brs).

[2-Amino-4,5-diphenylthiazole: Refer to “Nihon Kagaku Zasshi”, 1962,Vol. 83, p. 209.]

Example 205 Preparation of the Compound of Compound No. 205

Using 5-bromosalicylic acid and 2-amino-4-benzyl-5-phenylthiazole as theraw materials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 28.1%.

mp 198-200° C.

¹H-NMR(DMSO-d₆): δ 4.08(2H, s), 6.95(1H, d, J=8.8 Hz), 7.15-7.22(3H, m),7.30(2H, t, J=7.6 Hz), 7.38-7.43(1H, m), 7.47(4H, d, J=4.4 Hz), 7.57(1H,brd, J=8.8 Hz), 8.05(1H, d, J=2.4 Hz), 11.98(1H, brs).

[2-Amino-4-benzyl-5-phenylthiazole: Refer to “Chemical andPharmaceutical Bulletin”, 1962, Vol. 10, p. 376.]

Example 206 Preparation of the Compound of Compound No. 206

Using 5-bromosalicylic acid and2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials, thesame operation as the Example 195(3) gave the title compound.

Yield: 33.2%.

mp 250° C. (dec.).

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.8 Hz), 7.51(5H, s), 7.63(1H, dd,J=8.8, 2.4 Hz), 8.02(1H, d, J=2.8 Hz), 12.38(1H, brs).

Example 207 Preparation of the Compound of Compound No. 207

Using 1-phenyl-1,3-butanedione as the raw material, the same operationas the Examples 195(1)-(3) gave the title compound.

Yield: 8.9% (3 steps).

(1) α-Bromo-1-phenyl-1,3-butanedione

¹H-NMR(CDCl₃): δ 2.46(3H, s), 5.62(1H, s), 7.48-7.54(2H, m), 7.64(1H,tt, J=7.5, 2.1 Hz), 7.97-8.01(2H, m).

(2) 2-Amino-5-acetyl-4-phenylthiazole

¹H-NMR(DMSO-d₆): δ 2.18(3H, s), 7.50-7.55(2H, m), 7.59-7.68(3H, m),8.69(2H, brs).

(3) 5-Bromo-N-(5-acetyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 207)

¹H-NMR(DMSO-d₆): δ 2.44(3H, s), 6.99(1H, d, J=9.0 Hz), 7.55-7.71(4H, m),7.76-7.80(2H, m), 8.01(1H, d, J=2.4 Hz), 12.36(2H, br).

Example 208 Preparation of the Compound of Compound No. 208

Using 1,3-diphenyl-1,3-propanedione as the raw material, the sameoperation as the Examples 195(1)-(3) gave the title compound.

Yield: 49.7%.

(1) α-Bromo-1,3-diphenyl-1,3-propanedione

¹H-NMR(CDCl₃): δ 6.55(1H, s), 7.45-7.50(4H, m), 7.61(2H, tt, J=7.2, 2.1Hz), 7.98-8.01(4H, m).

(2) 2-Amino-5-benzoyl-4-phenylthiazole

¹H-NMR(DMSO-d₆): δ 7.04-7.18(5H, m), 7.22-7.32(3H, m), 7.35-7.38(2H, m),8.02(2H, s).

(3) 5-Bromo-N-(5-benzoyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide(Compound No. 208)

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.17-7.30(5H, m),7.39-7.47(3H, m), 7.57-7.60(2H, m), 7.64(1H, dd, J=8.7, 2.7 Hz),8.05(1H, d, J=2.4 Hz), 11.82(1H, brs), 12.35(1H, brs).

Example 209 Preparation of the Compound of Compound No. 210

Using 5-chlorosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylicacid ethyl ester as the raw materials, the same operation as the Example195(3) gave the title compound.

Yield: 69.4%.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.5 Hz), 4.21(2H, q, J=7.5 Hz),7.07(1H, d, J=8.7 Hz), 7.43-7.47(3H, m), 7.53(1H, dd, J=8.7, 2.4 Hz),7.70-7.74(2H, m), 7.92(1H, d, J=3.0 Hz), 11.88(1H, br), 12.29(1H, brs).

Example 210 Preparation of the Compound of Compound No. 209

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylicacid ethyl ester as the raw materials, the same operation as the Example195(3) gave the title compound.

Yield: 28.6%.

mp 197-199° C.

¹H-NMR(DMSO-d₆): δ 1.21(3H, t, J=6.8 Hz), 4.20(2H, q, J=6.8 Hz),7.01(1H, d, J=8.8 Hz), 7.43-7.48(3H, m), 7.63(1H, dd, J=8.8, 2.4 Hz),7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.33(1H, brs).

Example 211 Preparation of the Compound of Compound No. 211

Using pentafluorobenzoylacetic acid ethyl ester as the raw material, thesame operation as the Examples 195(1)-(3) gave the title compound.

Yield: 40.0% (3 steps).

(1) α-Bromo-pentafluorobenzoylacetic acid ethyl ester

It was used for the next reaction as a crude product.

(2) 2-Amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl ester

¹H-NMR(CDCl₃): δ 1.23(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 5.41(2H,s).

(3) Ethyl2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole-5-carboxylate(Compound No. 211)

¹H-NMR(DMSO-d₆): δ 1.20(3H, t, J=7.2 Hz), 2.51(2H, q, J=7.2 Hz),7.02(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.90(1H, d, J=3.0Hz), 11.92(1H, br), 12.58(1H, br).

Example 212 Preparation of the Compound of Compound No. 212 (1)2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid ethyl ester (compound No. 209) as the raw material, the sameoperation as the Example 82 gave the title compound.

Yield: 67.0%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.8 Hz), 7.42-7.44(3H, m), 7.62(1H, dd,J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.31(1H, brs),12.99(1H, brs).

(2)[2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazol-5-yl]-N-methylcarboxamide(Compound No. 212)

A mixure of2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid(0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml),1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg,0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperaturefor 18 hours. The reaction mixture was poured into 2N hydrochloric acidand extracted with ethyl acetate. After the organic layer was washedwith water and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation under reduced pressure was purified bychromatography on silica gel(n-hexane:ethyl acetate=1:2), andcrystallized (dichloromethane/n-hexane) to give the title compound (87.9mg, 42.6%) as a white powder.

¹H-NMR(DMSO-d₆): δ 2.70(3H, d, J=4.5 Hz), 7.02(1H, d, J=9.0 Hz),7.40-7.48(3H, m), 7.63(1H, dd, J=9.0, 2.4 Hz), 7.68-7.71(2H, m),8.06(1H, d, J=2.4 Hz), 8.16(1H, t, J=4.5 Hz), 11.88(1H, br), 12.15(1H,brs).

When the method described in Example 212(2) is referred in the followingexamples, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as thedehydrocondensating agent. As the reaction solvent, solvents such astetrahydrofuran or the like were used.

Example 213 Preparation of the Compound of Compound No. 213

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (compound of Example 212(1)) and 70% aqueous ethylamine solution asthe raw materials, the same operation as the Example 212(2) gave thetitle compound.

Yield: 62.5%.

¹H-NMR(DMSO-d₆): δ 1.05(3H, t, J=6.9 Hz), 3.15-3.24(2H, m), 7.02(1H, d,J=8.7 Hz), 7.40-7.47(3H, m), 7.63(1H, dd, J=8.7, 3.0 Hz), 7.69-7.72(2H,m), 8.06(1H, d, J=2.4 Hz), 8.20(1H, t, J=5.4 Hz), 11.84(1H, br),12.14(1H, brs).

Example 214 Preparation of the Compound of Compound No. 214

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (compound of Example 212(1)) and isopropylamine as the rawmaterials, the same operation as the Example 212(2) gave the titlecompound.

Yield: 23.9%.

¹H-NMR(DMSO-d₆): δ 1.07(6H, d, J=6.3 Hz), 4.02(1H, m), 7.02(1H, d, J=9.0Hz), 7.40-7.52(3H, m), 7.64(1H, dd, J=8.7, 2.7 Hz), 7.69-7.73(2H, m),8.06(1H, d, J=2.7 Hz), 11.89(1H, br), 12.14(1H, brs).

Example 215 Preparation of the Compound of Compound No. 215

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (compound of Example 212(1)) and 2-phenethylamine as the rawmaterials, the same operation as the Example 212(2) gave the titlecompound.

Yield: 62.2%.

¹H-NMR(DMSO-d₆): δ 2.78(2H, t, J=7.5 Hz), 3.43(2H, q, J=7.5 Hz),7.02(1H, d, J=9.0 Hz), 7.19-7.24(3H, m), 7.27-7.33(2H, m), 7.39-7.41(3H,m), 7.61-7.65(3H, m), 8.06(1H, d, J=2.4 Hz), 8.25(1H, t, J=6.0 Hz),11.85(1H, brs), 12.15(1H, brs).

Example 216 Preparation of the Compound of Compound No. 216

Using 5-bromosalicylic acid and2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester as theraw materials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 88.7%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=7.2 Hz), 4.33(2H, q, J=7.2 Hz),7.01(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.98(1H, d, J=2.4Hz), 12.64(1H, br).

Example 217 Preparation of the Compound of Compound No. 217

Using5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl}-2-hydroxybenzamide(compound No. 195) and acetyl chloride as the raw materials, the sameoperation as the Example 96 gave the title compound.

Yield: 65.3%.

¹H-NMR(CDCl₃): δ 1.32(9H, s), 1.33(9H,s),2.46(3H, s), 7.22(1H, d, J=8.4Hz), 7.56(1H, dd, J=8.7, 2.4 Hz), 8.05(1H, d, J=2.7 Hz), 9.82(1H, brs).

Example 218 Preparation of the Compound of Compound No. 218

Using 4-hydroxybiphenyl-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 61.7%.

mp 207-208° C.

¹H-NMR(DMSO-d₆): δ 1.23(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz),7.16(1H, d, J=8.7 Hz), 7.36(1H, t, J=7.5 Hz), 7.45-7.50(5H, m),7.69-7.76(4H, m), 7.85(1H, dd, J=8.7, 2.4 Hz), 8.31(1H, d, J=2.4 Hz),11.73(1H, brs), 12.60(1H, brs).

[4-Hydroxybiphenyl-3-carboxylic acid: Refer to “Tetrahedron”, 1997, Vol.53, p. 11437.]

Example 219 Preparation of the Compound of Compound No. 219

Using (4′-fluoro-4-hydroxybiphenyl)-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 62.7%.

mp 237-238° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.13(1H, d, J=8.4 Hz), 7.28(2H, t, J=8.8 Hz), 7.44-7.45(3H, m),7.71-7.75(4H, m), 7.81(1H, dd, J=8.8, 2.4 Hz), 8.27(1H, d, J=2.4 Hz),11.67(1H, brs), 12.58(1H, brs).

[(4′-Fluoro-4-hydroxybiphenyl)-3-carboxylic acid: Refer to“Tetrahedron”, 1997, Vol. 53, p. 11437.]

Example 220 Preparation of the Compound of Compound No. 220

Using (2′,4′-difluoro-4-hydroxybiphenyl)-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 45.6%.

mp 206-207° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7, 2 Hz),7.17(1H, d, J=9.0 Hz), 7.21(1H, td, J=8.7, 2.4 Hz), 7.38(1H, ddd,J=11.7, 9.3, 2.4 Hz), 7.44-7.46(3H, m), 7.60-7.75(4H, m), 8.13-8.14(1H,m), 11.86(1H, brs), 12.46(1H, brs).

Example 221 Preparation of the Compound of Compound No. 221 (1)[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid

A mixture of 5-bromosalicylic acid (500 mg, 2.30 mmol),dihydroxy-4-(trifluoromethyl)phenylborane (488 mg, 2.57 mmol), palladiumacetate (10 mg, 0.040 mmol) and 1M sodium carbonate (7 mL) was stirredat 80° C. for 1 hour. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. According to the fixed procedure, the obtained residue wasmethyl-esterified by trimethylsilyldiazomethane and methanol, andpurified by column chromatography on silica gel(n-hexane:ethylacetate=5:1) to give a colourless liquid (563 mg). This liquid wasdissolved in methanol (10 mL). 2N Sodium hydroxide (3 mL) was added, andthe mixture was stirred at 60° C. for 1 hour. After the reaction mixturewas cooled to room temperature, it was poured into 2N hydrochloric acidand extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and saturted brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure.The obtained residue was suspended and washed withn-hexane-dichloromethane under heating at reflux to give the titlecompound (458 mg, 70.4%) as a white crystal.

mp 185° C. (dec).

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.8 Hz), 7.77(2H, d, J=8.0 Hz),7.85(2H, d, J=8.0 Hz), 7.90(1H, dd, J=8.8, 2.0 Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).

(2)2-{[4-Hydroxy-4′-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylthiazole-5-carboxylicacid ethyl ester (Compound No. 221)

Using [4-hydroxy-4′-(trifluoromethyl)biphenyl]-3-carboxylic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 41.7%.

mp 236-237° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.18(1H, d, J=8.8 Hz), 7.44-7.45(3H, m), 7.72-7.74(2H, m), 7.81(2H, d,J=8.4 Hz), 7.91(1H, dd, J=8.8, 2.4 Hz), 7.93(2H, d, J=8.4 Hz), 8.36(1H,d, J=2.4 Hz), 11.78(1H, brs), 12.62(1H, brs).

Example 222 Preparation of the Compound of Compound No. 222

Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 55.0%.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz),6.26(2H, t, J=2.1 Hz), 7.13(1H, d, J=8.7 Hz), 7.32(2H, t, J=2.1 Hz),7.43-7.47(3H, m), 7.70-7.75(3H, m), 8.09(1H, d, J=2.7 Hz), 11.58(1H,brs), 12.55(1H, brs).

Example 223 Preparation of the Compound of Compound No. 223 (1)2-Hydroxy-5-(2-thienyl)benzoic acid

5-Bromosalicylic acid (500 mg, 2.30 mmol) was dissolved in1,2-dimethoxyethane (5 mL). Tetrakis(triphenylphosphine)palladium (80mg, 0.07 mmol) was added under argon atmosphere, and the mixture wasstirred at room temperature for 10 minutes. Thendihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1M sodium carbonate (7mL) were added, and the mixture was refluxed for 2 hours. After thereaction mixture was cooled to room temperature, it was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. According to the fixed procedure, the obtained residue wasmethyl-esterified by trimethylsilyldiazomethane and methanol, andpurified by column chromatography on silica gel(n-hexane:ethylacetate=5:1) to give an yellow liquid (277 mg). This was dissolved inmethanol (5 mL). 2N Sodium hydroxide (1.5 mL) was added, and the mixturewas stirred at 60° C. for 1 hour. After the reaction mixture was cooledto room temperature, it was poured into 2N hydrochloric acid andextracted with ethyl acetate. After the ethyl acetate layer was washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was crystallized from n-hexane-dichloromethane to givethe title compound (58 mg, 11.5%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 6.95(1H, d, J=8.8 Hz), 7.09(1H, dd, J=4.8, 3.6 Hz),7.37(1H, dd, J=4.0, 1.2 Hz), 7.45(1H, dd, J=5.2, 1.2 Hz), 7.74(1H, dd,J=8.8, 2.8 Hz), 7.96(1H, d, J=2.8 Hz).

(2)2-[2-Hydroxy-5-(2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylicacid ethyl ester (Compound No. 223)

Using 2-hydroxy-5-(2-thienyl)benzoic acid and2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the rawmaterials, the same operation as the Example 195(3) gave the titlecompound.

Yield: 58.2%.

mp 213-214° C.

¹H-NMR(DMSO-d₆): δ 1.22(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz),7.10(1H, d, J=9.2 Hz), 7.12(1H, dd, J=4.8, 3.6 Hz), 7.44-7.46(4H, m),7.50(1H, dd, J=4.8, 1.2 Hz), 7.71-7.74(2H, m), 7.79(1H, dd, J=8.8, 2.4Hz), 8.21(1H, d, J=2.4 Hz), 11.78(1H, brs), 12.44(1H, brs).

Example 301 Preparation of the Compound of Compound No. 301 (1)5-Chloro-2-methoxy-β-phenylstyrene

Palladium acetate (21 mg, 7mol %) was added to a solution of2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2 mmol),triethylamine (13 μL, 0.1 mmol) and triphenylphosphine (50 mg, 1.9 mmol)in acetonitrile (6 mL), and the mixture was refluxed for 8 hours underargon atmosphere. After the reaction mixture was cooled to roomtemperature, the solvent was concentrated under reduced pressure and theobtained residue was diluted with ethyl acetate (15 mL). After thesolution was washed successively with 2N hydrochloric acid, water andbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=10:1) to give thetitle compound (118 mg, 35.6%) as a white powder.

¹H-NMR(CDCl₃):d 3.85(3H, s), 6.80(1H, d, J=8.8 Hz), 7.08(1H, d, J=16.8Hz), 7.17(1H, dd, J=8.8, 2.5 Hz), 7.20-7.42(4H, m), 7.51-7.55(3H, m).

(2) 4-Chloro-2-styrylphenol (Compound No. 301)

Under argon atmosphere, 1 mol/L boron tribromide/dichloromethanesolution (0.5 mL, 0.5 mmol) was added to a solution of5-chloro-2-methoxy-β-phenylstyrene (80 mg, 0.3 mmol) in dichloromethane(2 mL) at room temperature, and the mixture was stirred for 12 hours.The reaction mixture was diluted with ethyl acetate (15 mL), and afterit was washed successively with water and brine, dried over anhydroussodium sulfate, the residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=3:1) to give the title compound (34.2 mg,45.4%) as a white powder.

¹H-NMR(CDCl₃):d 4.95(1H, brs), 6.74(1H, d, J=8.7 Hz), 7.09(1H, dd, =8.7,2.4 Hz), 7.10(1H, d, J=16.2 Hz), 7.28-7.39(4H, m), 7.49-7.54(3H, m).

Example 302 Preparation of the Compound of Compound No. 302 (1)(S)-2-Amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide

A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol),N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96 mmol),phosphorus trichloride (40 μL, 0.46 mmol) and toluene (4 mL) was stirredat 80° C. for 1.5 hours under argon atmosphere. After the reactionmixture was cooled to room temperature, it was poured into aqueoussodium hydrogen carbonate and extracted with ethyl acetate. After theethyl acetate layer was washed with brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was crystallized by isopropyl ether/n-hexane to givethe title compound (333.7 mg, 92.9%) as an yellow white powder.

¹H-NMR(DMSO-d₆): δ 3.13(1H, dd, J=13.8, 8.1 Hz), 3.29(1H, dd, J=13.8,6.0 Hz), 4.37(1H, s), 7.25-7.38(5H, m), 7.86(1H, s), 8.30(2H, s),8.48(3H, s), 11.95(1H, s).

When the method described in Example 302(1) is referred in the followingexamples, phosphorus trichloride was used as the acid halogenatingagent. As the reaction solvent, solvents such as toluene,monochlorobenzene or the like were used.

(2)(S)-2-Acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide

WSC.HCl (184 mg, 0.96 mmol) was added to a solution of2-acetoxy-5-chlorobenzoic acid (104 mg, 0.48 mmol),(S)-2-amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide(0.20 g, 0.48 mmol) and 1-hydroxybenzotriazole (71.4 mg, 0.53 mmol) inN,N-dimethylformamide (4 mL), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into dilutedhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed successively with water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=3:1→2:1) to give the title compound(141.4 mg, 51.4%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 2.05(3H, s), 3.04(1H, dd, J=13.8, 9.9 Hz), 3.19(1H,dd.J=13.8, 4.8 Hz), 4.73-4.81(1H, m), 7.22-7.35(6H, m), 7.54(1H, d,J=2.4 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz), 7.81(1H, s), 8.27(2H, s),8.91(1H, d, J=7.8 Hz), 10.81(1H, s).

When the method described in Example 302(2) is referred in the followingexamples, WSC.HCl and 1-hydroxybenzotriazole hydrate were used as thedehydrocondensating agent. As the reaction solvent, solvents such asN,N-dimethylformamide or the like were used.

(3)(S)-5-Chloro-2-hydroxy-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide(Compound No. 302)

5N Aqueous sodium hydroxide (0.2 mL) was added to a solution of(S)-2-acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-ethyl)benzamide(141.4 mg, 0.25 mmol) in a mixed solvent of methanol/tetrahydrofuran (2mL+2 mL), and the mixture was stirred at room temperature for 20minutes. The reaction mixture was poured into diluted hydrochloric acidand extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was crystallized by ethyl acetate/isopropylether/n-hexane to give the title compound (74.4 mg, 56.8%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 3.13(1H, dd, J=13.8, 9.0 Hz), 3.26(1H, dd, J=14.1,4.8 Hz), 4.85-4.92(1H, m), 6.95(1H, d, J=8.7 Hz), 7.19-7.23(1H, m),7.26-7.31(4H, m), 7.45(1H, dd, J=8.7, 2.4 Hz), 7.81(1H, s), 7.97(1H, d,J=2.4 Hz), 8.26(2H, s), 9.12(1H, d, J=7.2 Hz), 10.89(1H, s), 12.01(1H,s).

When the method described in Example 302(3) is referred in the followingexamples, inorganic bases such as sodium hydroxide, potassium carbonateor the like were used as the base. As the reaction solvent, solventssuch as water, methanol, ethanol, tetrahydrofuran or the like were usedalone or as a mixture.

Example 303 Preparation of the Compound of Compound No. 303 (1)[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic acid1,1-dimethyl ester

Under argon atmosphere, N-(tert-butoxycarbonyl)glycine (183.5 mg, 1.05mmol) and triethylamine (0.25 mL, 1.79 mmol) were added to a solution of3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol) in tetrahydrofuran(4 mL), and after cooling with ice bath, phosphorus oxychloride (96 μL,1.05 mmol) was added and the mixture was stirred at room temperature for5 hours. The reaction mixture was poured into water and extracted withethyl acetate. After the ethyl acetate layer was washed successivelywith water and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel(n-hexane:ethylacetate=2:1→3:2) to give the title compound (101.9 mg, 30.3%) as a whitecrystal.

¹H-NMR(CDCl₃): δ 1.49(9H, s), 3.99(2H, d, J=6.0 Hz), 5.37(1H, t, J=6.0Hz), 7.57(1H, s), 8.00(2H, s), 9.06(1H, brs).

(2) 2-Amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride

4N Hydrochloric acid/ethyl acetate solution (1 mL) was added to[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic acid1,1-dimethyl ester (101.9 mg, 0.26 mmol), and the mixture was stirred atroom temperature for 1 hour. n-Hexane (15 mL) was added to the reactionmixture and the separated white solid was filtered to give the titlecompound (80.8 mg, 96.4%) as a white powder.

¹H-NMR(CD₃OD): δ 3.89(2H, s), 7.71(1H, s), 8.22(2H, s).

(3)2-Acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-methyl)benzamide

WSC.HCl (95.9 mg, 0.5 mmol) was added to a solution of2-acetoxy-5-chlorobenzoic acid (59.1 mg, 0.28 mmol),2-amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride (80.8mg, 0.25 mmol) and 1-hydroxybenzotriazole (37.2 mg, 0.28 mmol) inN,N-dimethylformamide (3 mL), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into dilutedhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed with brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=3:2→1:1) to give the title compound (83.7 mg,69.3%) as a white crystal.

¹H-NMR(CDCl₃): δ 2.40(3H, s), 4.40(2H, d, J=5.4 Hz), 7.17(1H, d.J=8.4Hz), 7.40(1H, t, J=5.4 Hz), 7.53(1H, dd, J=8.4, 2.4 Hz), 7.62(1H, s),7.82(1H, d, J=2.4 Hz), 8.19(2H, s), 9.20(1H, s).

(4)5-Chloro-2-hydroxy-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-methyl)benzamide(Compound No. 303)

5N Aqueous sodium hydroxide (0.1 mL) was added to a solution of2-acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}methyl)benzamide(83.7 mg, 0.17 mmol) in methanol/tetrahydrofuran (2 mL+1 mL), and themixture was stirred at room temperature for 20 minutes. The reactionmixture was poured into diluted hydrochloric acid and extracted withethyl acetate. After the ethyl acetate layer was washed with water andbrine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=2:1) and washed withn-hexane under suspension to give the title compound (47.7 mg, 63.7%) asa white crystal.

¹H-NMR(DMSO-d₆): δ 4.18(2H, d, J=5.4 Hz), 7.00(1H, d, J=9.0 Hz),7.47(1H, dd, J=9.0, 2.7 Hz), 7.80(1H, s), 7.96(1H, d, J=2.7 Hz),8.27(2H, s), 9.25(1H, t, J=5.4 Hz), 10.78(1H, s), 12.14(1H, s).

Example 304 Preparation of the Compound of Compound No. 304 (1)5-Chlorosalicylhydrazide

A mixture of 5-chloro-2-hydroxybenzoic acid methyl ester (0.50 g, 2.7mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol) and ethanol (5 mL) wasrefluxed for 6 hours. After the reaction mixture was cooled to roomtemperature, n-hexane was added and the separated crystal was filteredto give the title compound (395.9 mg, 79.2%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 6.90(1H, d, J=8.7 Hz), 7.38(1H, dd, J=8.7, 2.7 Hz),7.85(1H, d, J=8.7 Hz), 10.23(brs).

(2) 5-Chlorosalicylic acid[3,5-bis(trifluoromethyl)benzylidene]hydrazide (Compound No. 304)

A mixture of 5-chlorosalicylhydrazide (213.9 mg, 1.2 mmol),3,5-bis(trifluoromethyl)benzaldehyde (190 μL, 1.2 mmol), concentratedsulfric acid (3 drops) and ethanol (5 mL) was refluxed for 30 minutes.3,5-Bis(trifluoromethyl)benzaldehyde (100 μL, 0.61 mmol) was added andthe mixture was refluxed for further 1 hour. After the reaction mixturewas cooled to room temperature, it was poured into water and extractedwith ethyl acetate. After the ethyl acetate layer was washed with brine,dried over sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=3:1→2:1) and washed with n-hexaneunder suspension to give the title compound (362.6 mg, 76.8%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.0 Hz), 7.49(1H, dd, J=9.0, 2.7 Hz),7.86(1H, d, J=3.0 Hz), 8.20(1H, s), 8.40(2H, s), 8.59(1H, s), 11.65(1H,s), 12.14(1H, s).

Example 305 Preparation of the compound of Compound No. 305 (1)(S)-2-Amino-4-methyl-N-[3,5-bis(trifluoromethyl)phenyl]pentanamide

Using N-(tert-butoxycarbonyl)-L-leucine and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 302(1) gave the title compound.

Yield: 25.2%.

¹H-NMR(CDCl₃): δ 0.98(3H, d, J=6.3 Hz), 1.01(3H, d, J=6.3 Hz),1.39-1.48(1H, 1.74-1.89(2H, m), 3.55(1H, dd, J=9.9, 3.6 Hz), 7.58(1H,s), 8.12(2H, s), 10.01(1H, s).

(2)(S)-5-Chloro-2-hydroxy-N-(3-methyl-1-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-butyl)benzamide(Compound No. 305)

Using 2-acetoxy-5-chlorobenzoic acid and(S)-2-amino-4-methyl-N-[3,5-bis-(trifluoromethyl)phenyl]pentanamide asthe raw materials, the same operation as the Example 302(2)-(3) gave thetitle compound.

Yield: 24.8% (2 steps).

¹H-NMR(DMSO-d₆): δ 0.95(3H, d, J=5.7Hz), 0.97(3H, d, J=6.0 Hz),1.65-1.84(3H, 4.65-4.72(1H, m), 6.98(1H, d, J=9.0 Hz), 7.47(1H, dd,J=8.7, 2.4Hz), 7.79(1H, s), 8.06(1H, d, J=2.7 Hz), 8.32(2H, s), 9.03(1H,d, J=8.1 Hz), 10.85(1H, s), 12.20(1H, s).

Example 306 Preparation of the Compound of Compound No. 306

Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)benzhydrazideas the raw materials, the same operation as the Example 304(2) gave thetitle compound.

Yield: 24.7%.

¹H-NMR(DMSO-d₆): δ 6.97(1H, d, J=8.7 Hz), 7.34(1H, dd, J=9.0, 2.7 Hz),7.73(1H, d, J=2.4 Hz), 8.41(1H, s), 8.59(2H, s), 8.67(1H, s), 11.07(1H,s), 12.45(1H, s).

Example 307 Preparation of the Compound of Compound No. 307

Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)phenethylamineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 30.2%.

¹H-NMR(CDCl₃): δ 3.10(2H, t, J=6.9 Hz), 3.71-3.77(2H, m), 6.34(1H, brs),6.95(1H, d, J=8.7 Hz), 7.23(1H, d, J=2.7 Hz), 7.36(1H, dd, J=8.7, 2.4Hz), 7.70(2H, s), 7.80(1H, s), 12.06(1H, s).

Example 308 Preparation of the Compound of Compound No. 308

A mixture of 3-hydroxyphthalic anhydride (100 mg, 0.6 mmol),3,5-bis(trifluoromethyl)aniline (168 mg, 0.7 mmol) and acetic acid (5mL) was refluxed for 6 hours under argon atmosphere. After the reactionmixture was cooled to room temperature, acetic acid was evaporated underreduced pressure and the obtained residue was dissolved in ethyl acetate(15 mL). After the ethyl acetate solution was washed successively withwater and brine, dried over anhydrous sodium sulfate, the residueobtained by evaporation of the solvent under reduced pressure waspurified by column chromatography on silica gel(n-hexane:ethylacetate=3:1) to give the title compound (100 mg, 43.7%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 7.31(1H, d, J=8.1 Hz),7.42(1H, d, J=7.5 Hz), 7.72(1H,dd, J=8.1, 7.5 Hz), 8.21(1H, s), 8.24(2H, s), 11.28(1H, s).

Example 309 Preparation of the Compound of Compound No. 309

3,5-Bis(trifluoromethyl)phenylisocyanate (180 μL, 1.04 mmol) was addedto a solution of 2-amino-4-chlorophenol (143.6 mg, 1 mmol) in a mixedsolvent of tetrahydrofuran/toluene (0.5 mL+4.5 mL), and the mixture wasstirred at 100° C. for 1 hour. After the reaction mixture was cooled toroom temperature, the residue obtained by evaporation of the solventunder reduced pressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=1:1) and crystallized by isopropylether/n-hexane to give the title compound (288.5 mg, 72.4%) as a lightyellowish brown powder.

¹H-NMR(DMSO-d₆): δ 6.84-6.91(2H, m),7.67(1H, s),8.06(2H, s), 8.14(1H, d,J=2.1 Hz), 8.45(1H, s), 10.10(1H, s), 10.44(1H, s).

Example 310 Preparation of the Compound of Compound No. 310 (1)5-Chloro-2-methoxy-β-[3,5-bis(trifluoromethyl)phenyl]styrene.

A solution of sodium nitrite (57 mg, 0.8 mmol) in water (1 mL) was addedto a solution of 2-amino-4-chloroanisole (131 mg, 0.8 mmol) in 48%hydrogen tetrafluoroborate (0.3 mL) under ice cooling and argonatmosphere. After the mixture was stirred at 0° C. for 1 hour, asolution of 3,5-bis(trifluoromethyl)styrene (100 mg, 0.4 mmol) inmethanol (3 mL) was added and the mixture was stirred at 50° C. for 1hour. After the reaction mixture was cooled to room temperature, theresidue obtained by evaporation of the solvent under reduced pressurewas diluted with ethyl acetate. After the solution was washedsuccessively with 2N hydrochloric acid, water and brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=5:1) to give the title compound (52.8mg, 33.3%) as a white powder.

¹H-NMR(CDCl₃): δ 3.85(3H, s), 6.80(1H, d, J=8.8 Hz), 7.08(1H, d, J=16.8Hz), 7.17(1H, dd, J=8.8, 2.5 Hz), 7.20-7.42(4H, m), 7.51-7.55(3H, m).

(2) 4-Chloro-2-[3,5-bis(trifluoromethyl)styryl]phenol (Compound No. 310)

Using 5-chloro-2-methoxy-β-[3,5-bis(trifluoromethyl)phenyl]styrene asthe raw material, the same operation as the Example 301(2) gave thetitle compound.

Yield: 18.1%.

¹H-NMR(CDCl₃): δ 5.16(1H, brs), 6.76(1H, d, J=8.4 Hz), 7.15(1H, dd,J=8.4, 2.7 Hz), 7.19(1H, d, J=16.5 Hz), 7.45(1H, d, J=15.5 Hz), 7.53(1H,d, J=2.4 Hz), 7.76(1H, s), 7.93(2H, s).

Example 311 Preparation of the Compound of Compound No. 311

Using 5-chlorosalicylic acid and 2-aminoindane as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 45.3%.

¹H-NMR(DMSO-d₆): δ 2.98(2H, dd, J=16.2, 5.7 Hz), 3.29(2H, dd, J=16.2,7.5 Hz), 4.69-4.79(1H, m), 6.93(1H, d, J=8.7 Hz), 7.16-7.20(2H, m),7.23-7.28(2H, m), 7.43(1H, dd, J=8.7, 2.4 Hz), 8.02(1H, d, J=2.4 Hz),9.03(1H, d, J=6.9 Hz), 12.66(1H, s).

Example 312 Preparation of the Compound of Compound No. 312 (1)4-Chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenol

Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 14(1) gave the titlecompound.

Yield: 76.6%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.50(1H, dd, J=9.0, 2.7 Hz),7.80(1H, d, J=2.7 Hz), 8.01(1H, s), 8.12(2H, s), 9.03(1H, s), 12.09(1H,brs).

(2) N-[(5-Chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline(Compound No. 312)

Using 4-chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenolas the raw material, the same operation as the Example 14(2) gave thetitle compound.

Yield: 78.1%.

¹H-NMR(CDCl₃): δ 4.40(3H, s), 6.27(1H, s), 6.80(1H, d, J=8.4 Hz),7.11(2H, s), 7.17-7.20(2H, m), 7.30(1H, s).

Example 313 Preparation of the Compound of Compound No. 313

WSC.HCl (138 mg, 0.7 mmol) was added to a solution ofN-[(5-chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline(Compound No. 312; 88.8 mg, 0.24 mmol) and acetic acid (43 mg, 0.7 mmol)in dichloromethane (2 mL) under argon atmosphere, and the mixture wasstirred at room temperature for 12 hours. After the reaction mixture wasdiluted with ethyl acetate, washed successively with water and brine,dried over anhydrous sodium sulfate, the residue obtained by evaporationof the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=3:1) to give thetitle compound (69 mg, 70.4%) as a white powder.

¹H-NMR(CDCl₃): δ 1.92(3H, s),4.73(2H, s), 6.54(1H, d, J=2.4 Hz),6.95(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.7, 2.4 Hz), 7.53(2H, s),7.99(1H, s), 9.21(1H, s).

Example 314 Preparation of the Compound of Compound No. 314

3,5-Bis(trifluoromethyl)benzoyl chloride (100 μL, 0.55 mmol) was addedto a solution of 5-chlorosalicyl hydrazide (compound of Example 304(1);0.1 g, 0.53 mmol) in pyridine (3 mL) and the mixture was stirred at roomtemperature for 6 hours. The reaction mixture was poured into 2Nhydrochloric acid and extracted with ethyl acetate. After the ethylacetate layer was washed with brine and dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was washed with ethyl acetate/isopropyl ether/n-hexaneunder suspension to give the title compound (169 mg, 74.7%) as a whitepowder.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.51(1H, dd, J=8.7, 2.4 Hz),7.92(1H, d, J=2.4 Hz), 8.43(1H, s), 8.57(2H, s), 10.79(1H, s), 11.37(1H,s), 11.81(1H, s).

Example 315 Preparation of the Compound of Compound No. 315

A mixture of 5-chlorosalicylhydrazide (compound of Example 304(1); 0.10g, 0.53 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (120 μL, 0.65mmol), triethylamine (0.2 mL, 1.43 mmol) and toluene (4 mL) was stirredat 100° C. for 2 hours. After the reaction mixture was cooled to roomtemperature, it was poured into diluted hydrochloric acid and extractedwith ethyl acetate. After the ethyl acetate layer was washed with brineand dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=3:1) andcrystallized by n-hexane to give the title compound (45.6 mg, 20.9%) asa white powder.

¹H-NMR(CDCl₃): δ 4.22(2H, d, J=4.8 Hz), 5.13(1H, q, J=4.8 Hz), 6.96(1H,d, J=8.7 Hz), 7.23(1H, d, J=2.4 Hz), 7.37(1H, dd, J=9.0, 2.4 Hz),7.69(1H, d, J=4.8 Hz), 7.85(1H, s), 7.88(2H, s), 11.54(1H, s).

Example 316 Preparation of the Compound of Compound No. 316

A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol),3,5-bis(trifluoromethyl)phenol (152 μL, 1 mmol), phosphorus oxychloride(40 μL, 0.43 mmol) and xylene (3 mL) was stirred at 140° C. for 2 hours.After the reaction mixture was cooled to room temperature, it was pouredinto water and extracted with ethyl acetate. After the ethyl acetatelayer was washed with brine and dried over anhydrous sodium sulfate, theresidue obtained by evaporation of the solvent under reduced pressurewas purified by column chromatography on silica gel(n-hexane:ethylacetate=10:1→5:1) to give the title compound (53.6 mg, 13.9%) as a whitecrystal.

¹H-NMR(CDCl₃): δ 7.04(1H, d, J=9.0 Hz), 7.54(1H, dd, J=9.0, 2.7 Hz),7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7 Hz), 10.09(1H, s).

Example 317 Preparation of the Compound of Compound No. 317

WSC.HCl (30.9 mg, 0.2 mmol) was added to a solution of 5-chlorosalicylicacid (35 mg, 0.2 mmol) and 3,5-bis(trifluoromethyl)phenylhydrazine (50mg, 0.2 mmol) in dichloromethane (2 mL) under argon atmosphere, and themixture was stirred at room temperature for 1 hour. After the reactionmixture was diluted with ethyl acetate, washed successively with waterand brine, dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=3:1) to give thetitle compound (56.3 mg, 69.6%) as a white powder.

¹H-NMR(CDCl₃): δ 6.61(1H, d, J=2.7 Hz), 6.99(1H, d, J=8.7 Hz), 7.28(2H,s), 7.41-7.45(2H, m), 7.62(1H, d, J=2.4 Hz), 8.53(1H, brs), 11.11(1H,s).

Example 318 Preparation of the Compound of Compound No. 318 (1)2-Bromo-1-(5-chloro-2-hydroxyphenyl)ethanone

Phenyltrimethylammonium tribromide (0.44 g, 1.17 mmol) was added to asolution of 5′-chloro-2′-hydroxyacetophenone (0.20 g, 1.17 mmol) intetrahydrofuran (6 mL) and the mixture was stirred at room temperaturefor 8 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. After the ethyl acetate layer was washed with brineand dried over anhydrous sodium sulfate, the residue obtained byevaporation of the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=5:1) to give thetitle compound (220.7 mg, 75.6%) as an yellow oil.

¹H-NMR(CDCl₃): δ 4.41(2H, s), 7.00(1H, d, J=9.3 Hz), 7.47(1H, dd, J=8.7,2.4 Hz), 7.71(1H, d, J=2.7 Hz), 11.63(1H, s).

(2) 2-(2-Aminothiazol-4-yl)-4-chlorophenol

A mixture of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethanone (156.9 mg,0.63 mmol), thiourea (47.9 mg, 0.63 mmol) and ethanol (3 mL) wasrefluxed for 2 hours. After the reaction mixture was cooled to roomtemperature, it was poured into saturated sodium hydrogen carbonatesolution and extracted with ethyl acetate. After the ethyl acetate layerwas washed with brine and dried over anhydrous sodium sulfate, theresidue obtained by evaporation of the solvent under reduced pressurewas purified by column chromatography on silica gel(n-hexane:ethylacetate=2:1) to give the title compound (98.6 mg, 64.5%) as a lightyellowish white powder.

¹H-NMR(DMSO-d₆): δ 6.85(1H, d, J=8.7 Hz), 7.14(1H, dd, J=8.7, 3.0 Hz),7.25(1H, s), 7.48(2H, s), 7.79(1H, d, J=3.0 Hz), 11.95(1H, s).

(3)N-[4-(5-Chloro-2-hydroxymethyl)thiazol-2-yl]-[3,5-bis(trifluoromethyl)phenyl]-benzamide(Compound No. 318)

Phosphorus trichloride (36 μL, 0.41 mmol) was added to a mixture of2-(2-aminothiazol-4-yl)-4-chlorophenol (98.6 mg, 0.41 mmol),3,5-bis(trifluoromethyl)benzoid acid (104.9 mg, 0.41 mmol),chlorobenzene (3 mL) and N-methyl-2-pyrrolidinone (3 mL), and themixture was refluxed for 3 hours. After the reaction mixture was cooledto room temperature, it was poured into water and extracted with ethylacetate. After the ethyl acetate layer was washed with brine and driedover anhydrous sodium sulfate, the residue obtained by evaporation ofthe solvent under reduced pressure was purified by column chromatographyon silica gel(n-hexane:ethyl acetate=4:1→2:1) and washed with isopropylether/n-hexane under suspension to give the title compound (19.6 mg,10.3%) as a white powder.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.4 Hz), 7.21(1H, dd, J=8.7, 2.7 Hz),7.95(1H, s), 8.08(1H, d, J=2.7 Hz), 8.45(1H, s), 8.77(2H, s), 10.90(1H,s), 13.15(1H, s).

Example 319 Preparation of the Compound of Compound No. 319 (1)3-[3,5-Bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione

5N Aqueous sodium hydroxide (0.5 mL) was added to a mixture of2,4-thiazolidinedione (198.7 mg, 1.69 mmol),3,5-bis(trifluoromethyl)benzyl bromide (0.50g, 1.63 mmol) and ethanol (5mL), and the mixture was refluxed for 4 hours. After the reactionmixture was cooled to room temperature, it was poured into water andextracted with ethyl acetate. After the ethyl acetate layer was washedwith brine and dried over anhydrous sodium sulfate, the residue obtainedby evaporation of the solvent under reduced pressure was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=3:1→2:1) togive the title compound (405.6 mg, 72.5%) as a white crystal.

¹H-NMR(CDCl₃): δ 4.01(2H, s), 4.87(2H, s), 7.84(1H, s), 7.86(2H, s).

(2)5-(5-Chloro-2-hydroxybenzylidene)-3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione(Compound No. 319)

A mixture of 3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione(0.20 g, 0.58 mmol), piperidine (3 drops), acetic acid (3 drops) andtoluene (5 mL) was stirred at room temperature for 10 minutes, then5-chlorosalicylaldehyde (92.3 mg, 0.59 mmol) was added and the mixturewas refluxed for 1 hour. After the reaction mixture was cooled to roomtemperature, it was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed with brine and dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=2:1→3:2) to give the title compound(173.2 mg, 62.0%) as a light yellow powder.

¹H-NMR(DMSO-d₆): δ 5.03(2H, s), 7.00(1H, d, J=9.0 Hz), 7.33(1H, d, J=2.4Hz), 7.38(1H, dd, J=8.7, 2.7 Hz), 8.03(1H, s), 8.05(2H, s), 8.07(1H, s),10.95(1H, s).

Example 320 Preparation of the Compound of Compound No. 320

A mixture of 3-hydroxyphthalic anhydride (33.5 mg, 0.2 mmol),3,5-bis(trifluoromethyl)benzyl amine (62 mg, 0.2 mmol) and chlorobenzene(5 mL) was refluxed for 3 hours under argon atmosphere. After thereaction mixture was cooled to room temperature, the solvent wasevaporated under reduced pressure and the obtained residue wascrystallized from n-hexane/ethyl acetate to give the title compound(68.5 mg, 85.2%) as a white crystal.

¹H-NMR(CDCl₃): δ 4.90(2H, s), 7.19(1H, dd, J=8.4, 0.6 Hz), 7.41(1H, dd,J=7.2, 0.6 Hz), 7.61(1H, dd, J=8.4, 7.2 Hz), 7.75(1H, brs), 7.82(1H,brs), 7.86(2H, s).

Example 321 Preparation of the Compound of Compound No. 321

A mixture of 5-chlorosalicylaldehyde (150 mg, 1 mmol),3,5-bis(trifluoromethyl)phenylhydrazine (200 mg, 0.9 mmol) and methanol(5 mL) was refluxed for 1 hour under argon atmosphere. After thereaction mixture was cooled to room temperature, methanol was evaporatedunder reduced pressure and the obtained residue was crystallized fromn-hexane/ethyl acetate to give the title compound (224 mg, 66.6%) as awhite powder.

¹H-NMR(CDCl₃): δ 6.97(1H, d, J=8.7 Hz), 7.17(1H,d,J=2.4 Hz), 7.24(1H,dd, J=9.0, 2.7 Hz), 7.35(2H, s), 7.41(1H, s), 7.82(1H, s), 7.87(1H, s),10.29(1H, s).

Example 322 Preparation of the Compound of Compound No. 322

Using 6-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 86.9%.

¹H-NMR(DMSO-d₆): δ 6.36(2H,d,J=8.4 Hz), 7.13(1H,t,J=8.4 Hz),7.79(1H,s),8.38(2H, s),11.40(2H,brs),11.96(1H, brs).

Example 323 Preparation of the Compound of Compound No. 323

Using 4-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 42.9%.

¹H-NMR(DMSO-d₆): δ 2.32(3H, s)6.82(1H, d, J=6.6 Hz)6.84(1H, s)7.83(1H,s)7.84(1H, d, J=8.5 Hz)8.47(2H, s)10.76(1H, s)11.44(1H, s).

Example 324 Preparation of the Compound of Compound No. 324

Using 5-bromo-4-hydroxysalicylic acid and3,5-bis(trifluoromethyl)aniline as the raw material, the same operationas the Example 16 gave the title compound.

Yield: 82.4%.

¹H-NMR(CDCl₃): δ 5.89(1H, s)6.70(1H, s)7.69(2H, s)7.95(1H, s)8.12(2H,s)11.62(1H, s).

Example 325 Preparation of the Compound of Compound No. 325

Using 4-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 29.9%.

¹H-NMR(DMSO-d₆): δ 6.37(1H, d, J=2.5 Hz), 6.42(1H, dd, J=8.8, 2.5 Hz),7.81(1H, s), 7.86(1H, d, J=8.5 Hz), 8.44(2H, s), 10.31(1H, s), 10.60(1H,s), 11.77(1H, s).

Example 326 Preparation of the Compound of Compound No. 326

Using 3,5-dichlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 7.85(1H, d, J=2.5 Hz), 7.91(1H, s), 8.01(1H, d, J=2.5Hz), 8.42(2H, s), 11.10(1H, s).

Example 327 Preparation of the Compound of Compound No. 327

Using 3-hydroxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 22.7%.

¹H-NMR(DMSO-d₆): δ 6.81(1H, t, J=8.0 Hz), 7.01(1H, dd, J=8.0, 1.5 Hz),7.35(1H, dd, J=8.0, 1.5 Hz), 7.84(1H, s), 8.46(2H, s), 9.56(1H, s),10.79(1H, s), 10.90(1H, brs).

Example 328 Preparation of the Compound of Compound No. 328

Using 3-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 54.9%.

¹H-NMR(DMSO-d₆): δ 2.22(3H, s), 6.94(1H, t, J=7.4 Hz), 7.42(1H, d, J=7.4Hz), 7.84-7.85(2H, m), 8.47(2H, s), 10.87(1H, s), 11.87(1H, s).

Example 329 Preparation of the Compound of Compound No. 329

Using 3-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 34.6%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 6.94(1H, t, J=8.0 Hz), 7.20(1H, dd,J=8.0, 1.4 Hz), 7.44(1H, dd, J=8.0, 1.4 Hz), 7.84(1H, s), 8.45(2H, s),10.82(1H, s), 10.94(1H, brs).

Example 330 Preparation of the Compound of Compound No. 330

Using 5-[(1,1,3,3-tetramethyl)butyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 64.2%.

¹H-NMR(DMSO-d₆): δ 0.70(9H, s), 1.35(6H, s), 1.72(2H, s), 6.95(1H, d,J=8.4 Hz), 7.50(1H, dd, J=8.0, 2.1 Hz), 7.83(1H, s), 7.84(1H, d, J=2.1Hz), 8.46(1H, s), 10.77(1H, s), 11.20(1H, s).

Example 331 Preparation of the Compound of Compound No. 331

Using 3,5,6-trichlorosalicylic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 26.2%.

¹H-NMR(DMSO-d₆): δ 7.88(1H, s), 7.93(1H, s), 8.33(2H, s), 10.88(1H, s),11.36(1H, s).

Example 332 Preparation of the Compound of Compound No. 332

Using 3,5-bis[(1,1-dimethyl)ethyl]salicylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 65.0%.

¹H-NMR(DMSO-d₆): δ 1.34(9H, s), 1.40(9H, s), 7.49(1H, d, J=2.2 Hz),7.82(1H, d, J=2.2 Hz), 7.91(1H, s), 8.40(2H, s), 10.82(1H, s), 12.44(1H,s).

Example 333 Preparation of the Compound of Compound No. 333

Using 6-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 35.9%.

¹H-NMR(DMSO-d₆): δ 6.73-6.82(2H, m), 7.32(1H, ddd, J=1.4, 8.5, 15.3 Hz),7.83(1H, s), 8.39(2H, s), 10.50(1H, d, J=1.4 Hz), 11.11(1H, s).

Example 334 Preparation of the Compound of Compound No. 334

Using 3-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 61.3%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, dd, J=7.6, 8.0 Hz), 7.69(1H, dd, J=1.4, 13.3Hz), 7.90(1H, s), 7.93(1H, dd, J=1.4, 8.0 Hz), 8.44(2H, s), 11.01(1H,s), 11.92(1H, br.s).

Example 335 Preparation of the Compound of Compound No. 335

Using 4-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 14.2%.

¹H-NMR(DMSO-d₆): δ 3.81(3H, s), 6.54(1H, d, J=2.5 Hz), 6.61(1H, dd,J=2.5, 8.8 Hz), 7.83(1H, s), 7.95(1H, d, J=8.8 Hz), 8.45(2H, s),10.69(1H, s), 11.89(1H, s).

Example 336 Preparation of the Compound of Compound No. 336

Using 6-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 63.1%.

¹H-NMR(DMSO-d₆): δ 3.24(3H, s), 6.03(1H, d, J=8.0 Hz), 6.05(1H, d, J=8.5Hz), 6.71(1H, dd, J=8.2, 8.5 Hz), 7.25(1H, s), 7.88(2H, s), 9.67(1H, s),10.31(1H, s)

Example 337 Preparation of the Compound of Compound No. 337

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 88) and methanesulfonyl chloride as the raw materials, thesame operation as the Example 91 gave the title compound.

Yield: 22.6%.

¹H-NMR(DMSO-d₆): δ 2.93(3H, s), 7.02(1H, d, J=8.4 Hz), 7.31(1H, dd,J=8.4, 2.7 Hz), 7.68(1H, d, J=2.7 Hz), 7.83(1H, s), 8.46(2H, s),9.48(1H, s), 10.85(1H, s), 11.15(1H, s).

Example 338 Preparation of the Compound of Compound No. 338

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 88) and benzenesulfonyl chloride as the raw materials, thesame operation as the Example 91 gave the title compound.

Yield: 45.3%.

¹H-NMR(DMSO-d₆): δ 6.89(1H, d, J=8.7 Hz), 7.10(1H, dd, J=8.7, 2.7 Hz),7.51-7.64(4H, m), 7.68-7.71(2H, m), 7.81(1H, s), 8.42(2H, s), 10.03(1H,s), 10.87(1H, s), 11.13(1H, brs).

Example 339 Preparation of the Compound of Compound No. 339

Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide(Compound No. 88) and acetyl chloride as the raw materials, the sameoperation as the Example 91 gave the title compound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 2.02(3H, s), 6.97(1H, d, J=8.7 Hz), 7.61(1H, dd,J=8.7, 2.7 Hz), 7.82(1H, s), 7.99(1H, d, J=2.7 Hz), 8.46(2H, s),9.90(1H, s), 10.85(1H, s), 10.94(1H, s).

Example 340 Preparation of the Compound of Compound No. 340

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide(compound of Example 87(2)) as the raw material, the same operation asthe Example 80(5) gave the title compound.

Yield: 59.9%.

¹H-NMR(DMSO-d₆): δ 7.17(1H, d, J=8.7 Hz), 7.31(2H, s), 7.85(1H, s),7.86(1H, dd, J=8.4, 2.4 Hz), 8.26(1H, d, J=2.7 Hz), 8.47(2H, s),10.95(1H, s), 11.90(1H, s).

Example 341 Preparation of the Compound of Compound No. 341

Using 3-hydroxynaphthalene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 46.9%.

¹H-NMR(DMSO-d₆): δ 7.36-7.41(2H, m), 7.50-7.55(1H, m), 7.79(1H, d, J=8.2Hz), 7.85(1H, d, J=0.6 Hz), 7.96(1H, d, J=8.0 Hz), 8.51(2H, s),10.98(1H, s), 11.05(1H, s).

Example 342 Preparation of the Compound of Compound No. 342

Using 2-hydroxynaphthalene-1-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 30.2%.

¹H-NMR(DMSO-d₆): δ 7.27(1H, d, J=8.8 Hz), 7.32-7.38(1H, m),7.45-7.50(1H, m), 7.72(1H, d, J=8.5 Hz), 7.82-7.93(3H, m), 8.50(1H, s),10.28(1H, s), 11.07(1H, brs).

Example 343 Preparation of the Compound of Compound No. 343 (1)4-Bromo-3-hydroxythiophene-2-carboxylic acid

A mixture of 4-bromothiophene-2-carboxylic acid methyl ester (500 mg,2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed solvent ofmethanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours. After thereaction mixture was cooled to room temperature, 2N hydrochloric acidwas added to adjust pH to 1, and it was diluted with ethyl acetate.After the ethyl acetate layer was washed successively with water andbrine, dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure to give the title compound (326 mg, 69.4%) as ared brown powder.

¹H-NMR(CDCl₃): δ 4.05(1H, brs), 7.40(1H, s).

(2)4-Bromo-3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-carboxamide(Compound No. 343)

Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and3,5-bis(trifluoromethyl)aniline as the raw materials, the same operationas the Example 16 gave the title compound.

Yield: 82.4%.

¹H-NMR(CDCl₃): δ 7.42(1H, s), 7.67(1H, brs), 7.78(1H, brs), 8.11(2H, s),9.91(1H, brs).

Example 344 Preparation of the Compound of Compound No. 344

Using 3,5-bis(trifluoromethyl)phenylisocyanate and oxindole as the rawmaterials, the same operation as the Example 28 gave the title compound.

Yield: 44.8%.

¹H-NMR(DMSO-d₆): δ 3.98(2H, s), 7.22(1H, td, J=7.8, 1.2 Hz),7.33-7.40(2H, m), 7.87(1H, s), 8.02(1H, d, J=7.8 Hz), 8.38(2H, s),11.00(1H, s).

Example 345 Preparation of the Compound of Compound No. 345

Using 3,5-bis(trifluoromethyl)phenylisocyanate and 5-chlorooxindole asthe raw materials, the same operation as the Example 28 gave the titlecompound.

Yield: 31.1%.

¹H-NMR(DMSO-d₆): δ 3.99(2H, s), 7.41(1H, dd, J=8.7, 2.4 Hz), 7.47(1H, d,J=2.1 Hz), 7.87(1H, s), 8.01(1H, d, J=8.4 Hz), 8.38(2H, s), 10.93(1H,s).

Example 346 Preparation of the Compound of Compound No. 346

Using 5-chlorosalicylic acid and 3-bromo-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 37.1%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz),7.72(1H, s), 7.84(1H, d, J=2.7 Hz), 8.16(1H, s), 8.28(1H, s), 10.69(1H,s), 11.42(1H, s).

Example 347 Preparation of the Compound of Compound No. 347

Using 5-chlorosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 68.0%.

¹H-NMR(DMSO-d₆): δ 3.85(3H, s), 7.02(1H, s), 7.03(1H, d, J=8.7 Hz),7.48(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s), 7.77(1H, s), 7.88(1H, d, J=2.7Hz), 10.57(1H, s), 11.53(1H, s).

Example 348 Preparation of the Compound of Compound No. 348

Using 5-chlorosalicylic acid and 2-morpholino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 64.8%.

¹H-NMR(DMSO-d₆): δ 2.90(4H, m), 3.84(4H, m), 7.15(1H, d, J=9.0 Hz),7.48(2H, s), 7.50(1H, dd, J=9.0, 2.7 Hz), 8.00(1H, d, J=2.7 Hz),8.91(1H, s), 11.24(1H, s), 12.05(1H, s).

Example 349 Preparation of the Compound of Compound No. 349

Using 5-chlorosalicylic acid and 2-bromo-5-(trifluoromethyl)aniline asthe raw material, the same operation as the Example 16 gave the titlecompound.

Yield: 59.2%.

¹H-NMR(DMSO-d₆): δ 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.4, 2.1 Hz),7.53(1H, dd, J=8.7, 3.0 Hz), 7.97-7.99(2H, m), 8.81(1H, d, J=2.1 Hz),11.03(1H, s), 12.38(1H, s).

Example 350 Preparation of the Compound of Compound No. 350

Using 5-chlorosalicylic acid and 3-amino-5-(trifluoromethyl)benzoic acidmethyl ester as the raw materials, the same operation as the Example 16gave the title compound.

Yield: 67.0%.

¹H-NMR(DMSO-d₆): δ 3.91(3H, s), 7.02(1H, d, J=9.3 Hz), 7.43(1H, dd,J=9.0, 2.4 Hz), 7.57(1H, d, J=2.4 Hz), 8.13(1H, s), 8.23(1H, s),8.29(1H, s), 8.36(1H, s), 11.52(1H, s).

Example 351 Preparation of the Compound of Compound No. 351

2N Aqueous sodium hydroxide (O.6 mL) was added to a mixture of5-chloro-2-hydroxy-N-[3-methoxycarbonyl-5-(trifluoromethyl)phenyl]benzamide(Compound No. 350; 105 mg, 0.281 mmol) and methanol (2.5 mL), and themixture was stirred at room temperature for 3 hours. Water was added tothe reaction mixture and it was washed with ethyl acetate. After thewater layer was acidified by addition of diluted hydrochloric acid, itwas extracted with ethyl acetate. After the ethyl acetate layer waswashed successively with water and brine, dried over anhydrous sodiumsulfate, the residue obtained by evaporation of the solvent underreduced pressure was crystallized by isopropyl ether to give the titlecompound (100 mg, 99.0%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz),7.91(1H, d, J=2.7 Hz), 7.93(1H, s), 8.43(1H, s), 8.59(1H, s), 10.78(1H,s), 11.48(1H, s).

Example 352 Preparation of the Compound of Compound No. 352

Using 5-chlorosalicylic acid and2-(2-naphthyloxy)-5-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 89.6%.

¹H-NMR(CDCl₃): δ 6.94(1H, d, J=9.6 Hz), 6.98(1H, d, J=9.2 Hz),7.25-7.41(4H, m), 7.48-7.57(3H, m), 7.81(1H, d, J=6.9 Hz), 7.88(1H, d,J=6.9 Hz), 7.95(1H, d, J=8.9 Hz), 8.72(1H, s), 8.83(1H, d, J=2.0 Hz),11.70(1H, s).

Example 353 Preparation of the Compound of Compound No. 353

Using 5-chlorosalicylic acid and2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)aniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 4.7%.

¹H-NMR(CDCl₃): δ 6.78(1H, d, J=8.9 Hz), 7.02(1H, d, J=8.6 Hz), 7.16(1H,d, J=8.6 Hz), 7.33-7.38(3H, m), 7.42(1H, dd, J=8.6, 2.6 Hz), 7.49(1H, d,J=2.6 Hz)7.58(1H, d, J=2.3 Hz), 8.66(1H, brs, ), 8.82(1H, d, J=2.0 Hz),11.65(1H, s).

Example 354 Preparation of the Compound of Compound No. 354

Using 5-chlorosalicylic acid and2-[(4-trifluoromethyl)piperidino]-5-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 60.5%.

¹H-NMR(CDCl₃): δ 1.85-2.05(2H, m), 2.15(2H, d, J=10.9 Hz), 2.28(1H, m),2.82(2H, t, J=11.0 Hz), 3.16(2H, d, J=12.2 Hz), 7.02(1H, d, J=8.9 Hz),7.31(1H, d, J=8.3 Hz), 7.42(2H, m), 7.50(1H, d, J=2.6 Hz), 8.75(1H, s),9.60(1H, s), 11.94(1H, s)

Example 355 Preparation of the Compound of Compound No. 355

Using 5-chlorosalicylic acid and2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 94.5%.

¹H-NMR(CDCl₃): δ 4.58(2H, q, J=7.9 Hz), 6.99-7.05(2H, m), 7.41-7.50(3H,m), 8.63(1H, brs), 8.79(1H, d, J=2.0 Hz), 11.59(1H, s).

Example 356 Preparation of the Compound of Compound No. 356

Using 5-chlorosalicylic acid and2-(2-methoxyphenoxy)-5-(trifluoromethyl)aniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 80.6%.

¹H-NMR(DMSO-d₆): δ 3.74(3H, s), 6.70(1H, d, J=8.4 Hz), 7.02(1H, d, J=8.7Hz), 7.07(1H, dd, J=1.5, 7.8 Hz), 7.24-7.39(4H, m), 7.49(1H, dd, J=3.0,8.7 Hz), 8.00(1H, d, J=3.0 Hz), 8.92(1H, d, J=2.1 Hz), 11.36(1H, s),12.18(1H, s).

Example 357 Preparation of the Compound of Compound No. 357

Using 5-chlorosalicylic acid and2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 91.5%.

¹H-NMR(DMSO-d₆): δ 2.34(6H, s), 7.03(1H, d, J=8.8 Hz), 7.05(1H, d, J=8.1Hz), 7.11(2H, s), 7.43-7.47(1H, m), 7.48(1H, dd, J=2.9, 8.8 Hz),7.97(1H, d, J=2.6 Hz), 8.94(1H, d, J=2.2 Hz), 11.25(1H, s), 12.12(1H,s).

Example 358 Preparation of the Compound of Compound No. 358

Using 5-chlorosalicylic acid and 2-piperidino-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 73.7%.

¹H-NMR(CDCl₃): δ 1.68-1.72(2H, m), 1.80-1.88(4H, m), 2.89(4H, t, J=5.2Hz), 7.01(1H, d, J=8.7 Hz), 7.31(1H, d, J=8.4 Hz), 7.39-7.43(2H, m),7.55(1H, d, J=2.4 Hz), 8.73(1H, d, J=1.8 Hz), 9.71(1H, s), 12.05(1H, s)

Example 359 Preparation of the Compound of Compound No. 359

Using 5-chlorosalicylic acid and2-(4-methylphenoxy)-5-(trifluoromethyl)-aniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 67.3%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 6.93(1H, d, J=8.8 Hz), 7.03(1H, dd,J=0.5, 8.8 Hz), 7.12(2H, d, J=8.2 Hz), 7.29(2H, d, J=8.5 Hz), 7.43(1H,dd, J=2.0, 8.6 Hz), 7.48(1H, ddd, J=0.8, 2.7, 8.8 Hz), 7.98(1H, dd,J=0.8, 2.7 Hz), 8.94(1H, d, J=2.2 Hz), 11.29(1H, s), 12.15(1H, s).

Example 360 Preparation of the Compound of Compound No. 360

Using 5-chlorosalicylic acid and2-(4-chlorophenoxy)-5-(trifluoromethyl)-aniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 74.5%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=8.8 Hz), 7.06(1H, d, J=8.5 Hz),7.22(1H, d, J=8.5 Hz), 7.43-7.48(2H, m), 7.50(2H, d, J=8.2 Hz), 7.94(1H,dd, J=0.5, 2.7 Hz), 8.92(1H, d, J=2.2 Hz), 11.20(1H, s), 12.10(1H, s).

Example 361 Preparation of the Compound of Compound No. 361

Using 5-bromo-2-hydroxy-N-[3,5-bis(methoxycarbonyl)phenyl]benzamide(Compound No. 170) as the raw material, the same operation as theExample 351 gave the title compound.

Yield: 89.0%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.7 Hz), 7.60(1H, dd, J=8.7, 2.4 Hz),7.24(1H, dd, J=8.7, 2.7 Hz), 8.08(1H, d, J=2.7 Hz), 8.24(1H, t, J=1.5Hz), 8.57(2H, d, J=1.2 Hz), 10.67(1H, s), 11.64(1H, s).

Example 362 Preparation of the Compound of Compound No. 362

Using 5-chlorosalicylic acid and 2-methyl-5-[(1-methyl)ethyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 19.1%.

¹H-NMR(CDCl₃): δ 1.26(6H, d, J=6.9 Hz), 2.30(3H, s), 2.87-2.96(1H, m),7.00(1H, d, J=8.7 Hz), 7.08(1H, dd, J=7.8, 1.8 Hz), 7.20(1H, d, J=7.8Hz), 7.40(1H, dd, J=8.7, 2.4 Hz), 7.49(1H, d, J=2.7 Hz), 7.50(1H, s),7.71(1H, s), 11.99(1H, s).

Example 363 Preparation of the Compound of Compound No. 363

Using 5-chlorosalicylic acid and 2,5-diethoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 59.2%.

¹H-NMR(DMSO-d₆): δ 1.32(3H, t, J=6.9 Hz), 1.41(3H, t, J=6.9 Hz),3.97(2H,q, J=6.9 Hz), 4.06(2H, q, J=6.9 Hz), 6.61(1H, dd, J=9.0, 3.0 Hz),6.98(1H, d, J=8.7 Hz), 7.10(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7Hz), 7.97(1H, d, J=2.7 Hz), 8.16(1H, d, J=3.0 Hz), 10.96(1H, s),11.91(1H, s).

Example 364 Preparation of the Compound of Compound No. 364

Using 5-chlorosalicylic acid and 2,5-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 90.5%.

¹H-NMR(CDCl₃): δ 2.28(3H, s), 2.35(3H, s), 6.99(1H, d, J=8.8 Hz),7.02(1H, brs), 7.15(1H, d, J=7.7 Hz), 7.40(1H, dd, J=8.8, 2.5 Hz),7.45(1H, brs), 7.49(1H, d, J=2.5 Hz)7.70(1H, br), 11.96(1H, brs).

Example 365 Preparation of the Compound of Compound No. 365

Using 5-chlorosalicylic acid and 5-chloro-2-cyanoaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 90.0%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz),7.82(1H, dd, J=8.7, 2.4 Hz), 7.95(1H, d, J=3.0 Hz), 8.07(1H, d, J=2.4Hz), 8.36(1H, d, J=9.0 Hz), 11.11(1H, s), 12.36(1H, s).

Example 366 Preparation of the Compound of Compound No. 366

Using 5-chlorosalicylic acid and5-(N,N-diethylsulfamoyl)-2-methoxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 44.8%.

¹H-NMR(CDCl₃): δ 1.17(6H, t, J=7.3 Hz), 3.29(4H, q, J=7.3 Hz), 4.05(3H,s), 7.00(2H, dd, J=2.3, 8.9 Hz), 7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H,d, J=2.6 Hz), 7.65(1H, dd, J=2.3, 8.6 Hz), 8.56(1H, br.s), 8.84(1H, d,J=2.3 Hz), 11.82(1H, s).

Example 367 Preparation of the Compound of Compound No. 367

Using 5-chlorosalicylic acid and 2-chloro-5-nitroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 73.3%.

¹H-NMR(CD₃OD): δ 6.98(1H, d, J=8.6 Hz), 7.43(1H, dd, J=2.6, 8.6 Hz),7.74(1H, d, J=8.9 Hz), 7.99(1H, dd, J=3.0, 8.9 Hz), 8.08(1H, d, J=2.6Hz), 9.51(1H, d, J=2.6 Hz).

Example 368 Preparation of the Compound of Compound No. 368

Using 5-chlorosalicylic acid and 5-(N-phenylcarbamoyl)-2-methoxyanilineas the raw material, the same operation as the Example 16 gave the titlecompound.

Yield: 40.3%.

¹H-NMR(DMSO-d₆): δ 3.99(3H, s), 7.09(2H, dd, J=6.6, 6.9 Hz), 7.24(1H, d,J=8.6 Hz), 7.35(2H, dd, 6.9, 7.3 Hz), 7.49(1H, d, J=2.3, 8.9 Hz),7.77(3H, d, J=8.6 Hz), 8.00(1H, s), 8.97(1H, s), 10.17(1H, s), 10.91(1H,s), 12.11(1H, s).

Example 369 Preparation of the Compound of Compound No. 369

Using 5-chlorosalicylic acid and 2,5-dimethoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 73.9%.

¹H-NMR(CDCl₃): δ 3.82(3H, s), 3.93(3H, s), 6.66(1H, dd, J=3.0, 8.9 Hz),6.86(1H, d, J=8.9 Hz), 6.98(1H, d, J=8.9 Hz), 7.39(1H, dd, J=2.6, 8.9Hz), 7.47(1H, d, J=2.6 Hz), 8.08(1H, d, J=3.0 Hz), 8.60(1H, br.s),12.03(1H, s).

Example 370 Preparation of the Compound of Compound No. 370

Using 5-chlorosalicylic acid and 5-acetylamino-2-methoxyaniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 16.9%.

¹H-NMR(DMSO-d₆): δ 2.01(3H, s), 3.85(3H, s), 7.03(2H, t, J=9.6 Hz),7.49(2H, dd, J=8.9, 9.2 Hz), 7.96(1H, s), 8.51(1H, s), 9.87(1H, s),10.82(1H, s), 12.03(1H, d, J=4.0 Hz).

Example 371 Preparation of the Compound of Compound No. 371

Using 5-chlorosalicylic acid and 5-methoxy-2-methylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 100%.

¹H-NMR(CDCl₃): δ 2.29(3H, s), 3.82(3H, s), 6.75(1H, dd, J=2.6, 8.2 Hz),7.00(1H, d, J=8.9 Hz), 7.16(1H, d, J=8.6 Hz), 7.38(1H, d, 2.3 Hz),7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H, d, J=2.3 Hz), 7.70(1H, br.s),11.92(1H, s).

Example 372 Preparation of the Compound of Compound No. 372

Using 5-chlorosalicylic acid and 2,5-dibutoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 73.9%.

¹H-NMR(CDCl₃): δ 0.98(3H, t, J=7.2 Hz), 1.05(3H, t, J=7.2 Hz),1.44-1.65(4H, m), 1.72-1.79(2H, m), 1.81-1.91(2H, m), 3.97(2H, t, J=6.3Hz), 4.07(2H, t, J=6.3 Hz), 6.64(1H, dd, J=9.0, 3.0 Hz), 6.85(1H, d,J=9.3 Hz), 6.99(1H, d, J=9.0 Hz), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.44(1H,d, J=2.7 Hz), 8.08(1H, d, J=3.0 Hz), 8.76(1H, s), 12.08(1H, s).

Example 373 Preparation of the Compound of Compound No. 373

Using 5-chlorosalicylic acid and 2,5-diisopentyloxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 59.7%.

¹H-NMR(CDCl₃): δ 0.97(6H, d, J=6.6 Hz), 1.03(6H, d, 6.6 Hz),1.64-1.98(6H, m), 3.99(2H, t, J=6.6 Hz), 4.09(2H, t, J=6.3 Hz), 6.63(1H,dd, J=8.7, 3.0 Hz), 6.85(1H, d, J=8.7 Hz), 6.98(1H, d, J=8.7 Hz),7.38(1H, dd, J=9.0, 2.4 Hz), 7.43(1H, d, J=2.7 Hz), 8.09(1H, d, J=3.0Hz), 8.75(1H, s), 12.08(1H, s).

Example 374 Preparation of the Compound of Compound No. 374

Using 5-chlorosalicylic acid and 5-carbamoyl-2-methoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 31.2%.

¹H-NMR(CD₃OD): δ 4.86(3H, s), 6.93(1H, d, J=7.6 Hz), 7.18(1H, d, J=8.6Hz), 7.35(1H, dd, J=3.0, 7.6 Hz), 7.47(1H, dd, J=2.0, 8.6 Hz), 8.00(1H,d, J=3.0 Hz), 8.80(1H, d, J=2.0 Hz).

Example 375 Preparation of the Compound of Compound No. 375

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)propyl]-2-phenoxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 65.2%.

¹H-NMR(CDCl₃): δ 0.69(3H, t, J=7.6 Hz), 1.29(6H, s), 1.64(2H, q, J=7.6Hz), 6.91(1H, dd, J=1.7, 7.6 Hz), 6.96(1H, d, J=8.9 Hz), 7.03(2H, d,J=8.9 Hz), 7.10(1H, dt, J=1.7, 7.6 Hz), 7.16(1H, dt, J=1.7, 7.6 Hz),7.40-7.31(4H, m), 8.42(1H, dd, J=2.0, 7.9 Hz), 8.53(1H, br.s)11.94(1H,s).

Example 376 Preparation of the Compound of Compound No. 376

Using 5-chlorosalicylic acid and 2-hexyloxy-5-(methylsulfonyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 33.0%.

¹H-NMR(CDCl₃): δ 0.92(3H, t, J=6.9 Hz), 1.40-1.59(6H, m), 1.90-2.01(2H,m), 3.09(3H, s), 4.22(2H, t, J=6.3 Hz), 7.01(1H, d, J=8.9 Hz), 7.06(1H,d, J=8.6 Hz), 7.40-7.43(2H, m), 7.73(1H, dd, J=8.6, 2.3 Hz), 8.74(1H,brs), 8.99(1H, d, J=2.3 Hz), 11.76(1H, s).

Example 377 Preparation of the Compound of Compound No. 377

Using 5-chlorosalicylic acid and 3′-amino-2,2,4′-trimethylpropiophenoneas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 44.8%.

¹H-NMR(CDCl₃): δ 1.38(9H, s),2.38(3H, s),7.01(1H, d, J=8.9 Hz), 7.31(1H,d, J=7.9 Hz), 7.42(1H, dd, J=8.9, 2.6 Hz), 7.53(1H, d, J=2.6 Hz),7.57(1H, dd, J=7.9, 2.0 Hz), 7.83(1H, brs), 8.11(1H, d, J=2.0 Hz),11.82(1H, s).

Example 378 Preparation of the Compound of Compound No. 378

Using 5-chlorosalicylic acid and 5-methoxy-2-(1-pyrrolyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 53.4%.

¹H-NMR(CDCl₃): δ 2.46(3H, s), 6.51-6.52(2H, m), 6.82-6.85(3H, m),6.93(1H, d, J=8.9 Hz), 7.06(1H, d, J=7.9 Hz), 7.30(1H, d, J=7.9 Hz),7.32(1H, dd, J=2.3, 8.9 Hz), 7.61(1H, s), 8.29(1H, s), 11.86(1H, br.s).

Example 379 Preparation of the Compound of Compound No. 379

Using 5-chlorosalicylic acid and 5-chloro-2-tosylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 8.0%.

¹H-NMR(CDCl₃): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.25-7.31(3H, m),7.46(1H, dd, J=2.6, 8.9 Hz), 7.68(2H, d, J=8.6 Hz), 7.74(1H, d, J=2.3Hz), 7.96(1H, d, J=8.6 Hz), 8.56(1H, d, J=2.0 Hz), 10.75(1H, s),11.70(1H, s).

Example 380 Preparation of the Compound of Compound No. 380

Using 5-chlorosalicylic acid and 2-chloro-5-tosylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 43.5%.

¹H-NMR(CDCl₃): δ 2.38(3H, s), 7.02(1H, d, J=8.9 Hz), 7.27(1H, d, J=7.9Hz), 7.29(1H, dd, J=2.0, 6.6 Hz), 7.46(1H, dd, J=2.3, 8.9 Hz), 7.68(2H,d, J=8.6 Hz), 7.73(2H, d, J=2.3 Hz), 7.97(1H, d, J=8.6 Hz), 8.56(1H, d,J=2.0 Hz), 10.73(1H, s), 11.71(1H, s).

Example 381 Preparation of the Compound of Compound No. 381

Using 5-chlorosalicylic acid and 2-fluoro-5-(methylsulfonyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 28.8%.

¹H-NMR(CDCl₃): δ 3.12(3H, s), 7.03(1H, d, J=8.9 Hz), 7.38(1H, dd, J=8.6,10.2 Hz), 7.45(1H, dd, J=2.3, 8.9 Hz), 7.53(1H, d, J=2.3 Hz), 7.80(1H,ddd, J=2.3, 4.6, 8.6 Hz), 8.25(1H, s), 8.98(1H, dd, J=2.3, 7.7 Hz),11.33(1H, br.s).

Example 382 Preparation of the Compound of Compound No. 382

Using 5-chlorosalicylic acid and 2-methoxy-5-phenoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 77.0%.

¹H-NMR(CDCl₃): δ 3.98(3H, s), 6.80(1H, d, J=8.8 Hz), 6.90(1H, d, J=8.8Hz), 6.95-7.00(3H, m), 7.04-7.09(1H, m), 7.29-7.35(2H, m), 7.38(1H, dd,J=8.8, 2.6 Hz), 7.47(1H, d, J=2.6 Hz), 8.19(1H, d, J=2.9 Hz), 8.61(1H,brs), 11.92(1H, s).

Example 383 Preparation of the Compound of Compound No. 383

Using 5-chlorosalicylic acid and 3-amino-4-methylbiphenyl as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 47.7%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 7.06(1H, d, J=8.7 Hz), 7.43-7.52(4H, m),7.64-7.67(2H, m), 8.04(1H, d, J=2.7 Hz), 8.19(1H, d, J=1.5 Hz),10.40(1H, s), 12.22(1H, s).

Example 384 Preparation of the Compound of Compound No. 384

Using 5-chlorosalicylic acid and 5-( a, a-dimethylbenzyl)-2-methoxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 89.0%.

¹H-NMR(CDCl₃): δ 1.72(6H, s), 3.93(3H, s), 6.83(1H, d, J=8.8 Hz),6.93(1H, dd, J=2.6, 8.8 Hz), 6.96(1H, d, J=9.2 Hz), 7.15-7.20(1H, m),7.25-7.28(4H, m), 7.36(1H, dd, J=2.6, 8.8 Hz), 7.46(1H, d, J=2.6 Hz),8.35(1H, d, J=2.6 Hz), 8.51(1H, s), 12.04(1H, s).

Example 385 Preparation of the Compound of Compound No. 385

Using 5-chlorosalicylic acid and 5-morpholino-2-nitroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 4.1%.

¹H-NMR(DMSO-d₆): δ 3.46-3.52(4H, m), 3.85-3.94(4H, m), 7.03(1H, d, J=8.8Hz), 7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H,d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2 Hz), 10.70(1H,s), 11.43(1H, s)

Example 386 Preparation of the Compound of Compound No. 386

Using 5-chlorosalicylic acid and 5-fluoro-2-(1-imidazolyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 33.8%.

¹H-NMR(DMSO-d₆): δ 6.99(1H, d, J=8.8 Hz), 7.12-7.19(2H, m),7.42-7.51(3H, m), 7.89(1H, d, J=2.8 Hz), 7.93(1H, d, J=1.1 Hz), 8.34(1H,dd, J=11.4, 2.8 Hz), 10.39(1H, s), 11.76(1H, brs).

Example 387 Preparation of the Compound of Compound No. 387

Using 5-chlorosalicylic acid and 2-butyl-5-nitroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 15.3%.

¹H-NMR(CDCl₃): δ 0.99(3H, t, J=7.3 Hz), 1.39-1.51(2H, m), 1.59-1.73(2H,m), 2.71-2.79(2H, m), 7.03(1H, d, J=8.9 Hz), 7.41-7.49(3H, m), 7.92(1H,s), 8.07(1H, dd, J=2.3, 8.4 Hz), 8.75(1H, d, J=2.4 Hz), 11.51(1H, s).

Example 388 Preparation of the Compound of Compound No. 388

Using 5-chlorosalicylic acid and5-[(1,1-dimethyl)propyl]-2-hydroxyaniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 36.0%.

¹H-NMR(CDCl₃): δ 0.70(3H, t, J=7.4 Hz), 1.28(6H, s), 1.63(2H, q, J=7.4Hz), 6.97(1H, d, J=6.3 Hz), 7.00(1H, d, J=6.6 Hz), 7.08(1H, s), 7.14(1H,dd, J=2.5, 8.6 Hz), 7.36(1H, d, J=2.2 Hz), 7.42(1H, dd, J=2.5, 8.8 Hz),7.57(1H, d, J=2.5 Hz), 8.28(1H, s), 11.44(1H, s).

Example 389 Preparation of the Compound of Compound No. 389

Using 5-chlorosalicylic acid and 2-methoxy-5-methylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 74.2%.

¹H-NMR(DMSO-d₆): δ 2.27(3H, s), 3.85(3H, s), 6.90(1H, dd, J=9.0, 2.4Hz), 6.98(1H, d, J=9.0 Hz), 7.05(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0,3.0 Hz), 7.97(1H, d, J=3.0 Hz), 8.24(1H, d, J=2.4 Hz), 10.79(1H, s),12.03(1H, s).

Example 390 Preparation of the Compound of Compound No. 390

Using 5-chlorosalicylic acid and 2,5-difluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 81.5%.

¹H-NMR(DMSO-d₆): δ 6.98-7.07(1H, m), 7.07(1H, d, J=9.0 Hz),7.37-7.49(1H, m), 7.52(1H, dd, J=8.7, 3.0 Hz), 7.95(1H, d, J=2.7 Hz),8.15-8.22(1H, m), 10.83(1H, s), 12.25(1H, s).

Example 391 Preparation of the Compound of Compound No. 391

Using 5-chlorosalicylic acid and 3,5-difluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 82.0%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, tt, J=9.3, 2.1), 7.03(1H, d, J=9.0 Hz),7.47(1H, dd, J=7.5, 2.7 Hz), 7.49(1H, d, J=2.7 Hz), 7.51(1H, d, J=2.1Hz), 7.82(1H, d, J=3.0 Hz), 10.63(1H, s), 11.43(1H, brs).

Example 392 Preparation of the Compound of Compound No. 392

Using2-(5-bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylicacid ethyl ester (Compound No. 197) as the raw material, the sameoperation as the Example 82 gave the title compound.

Yield: 85.5%.

¹H-NMR(DMSO-d₆): δ 1.44(9H, s), 7.00(1H, d, J=9.0 Hz), 7.62(1H, dd,J=9.0, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.83(1H, brs), 12.04(1H, brs),12.98(1H, brs).

Example 393 Preparation of the Compound of Compound No. 393

Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acidmethyl ester as the raw materials, the same operation as the Example195(3) gave the title compound. (This compound is the compound ofExample 203(1).)

Yield: 32.1%.

mp 288.5-229.5° C.

¹H-NMR(DMSO-d₆): δ 3.66(3H, s), 3.95(2H, s), 6.99(1H, d, J=8.0 Hz),7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6 Hz), 7.56-7.61(3H,m),8.07(1H, d, J=2.4 Hz), 11.85(1H, brs), 11.98(1H, brs).

Example 394 Preparation of the Compound of Compound No. 394

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid ethyl ester (Compound No. 209) as the raw material, the sameoperation as the Example 82 gave the title compound. (This compound isthe compound of Example 212(1).)

Yield: 67.0%.

¹H-NMR(DMSO-d₆): δ 7.00(1H, d, J=8.8 Hz), 7.42-7.44(3H, m), 7.62(1H, dd,J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4 Hz), 12.31(1H, brs),12.99(1H, brs).

Example 395 Preparation of the Compound of Compound No. 395 (1)2-Amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole

Phenyltrimethylammonium tribromide (753 mg, 2 mmol) was added to asolution of 3′,5′-bis(trifluoromethyl)acetophenone (0.51 g, 2.0 mmol) intetrahydrofuran (5 mL) and the mixture was stirred at room temperaturefor 5 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. After the ethyl acetate layer was washed with brine,dried over anhydrous sodium sulfate, ethanol (5 mL) and thiourea (152mg, 2 mmol) were added to the residue obtained by evaporation of thesolvent under reduced pressure, and the mixture was refluxed for 30minutes. After the reaction mixture was cooled to room temperature, itwas poured into saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate. After the ethyl acetate layer was washedwith brine and dried over anhydrous sodium sulfate, the residue obtainedby evaporation of the solvent under reduced pressure was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=2:1) andwashed with n-hexane under suspension to give the title compound (520.1mg, 83.3%) as a light yellow white crystal.

¹H-NMR(CDCl₃): δ 5.03(2H, s), 6.93(1H, s), 7.77(1H, s), 8.23(2H, s).

(2)5-Chloro-2-hydroxy-N-{4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 395)

A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol),2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole(312.2 mg, 1 mmol),phosphorus trichloride (44 μL, 0.5 mmol) and monochlorobenzene (5 mL)was refluxed for 4 hours. After the reaction mixture was cooled to roomtemperature, it was poured into water and extracted with ethyl acetate.After the ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate, the residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=3:1→2:1) to give the title compound(109.8 mg, 23.5%) as a pale yellow white powder.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz),7.94(1H, d, J=3.0 Hz), 8.07(1H, s), 8.29(1H, s), 8.60(2H, s), 11.77(1H,s), 12.23(1H, s).

Example 396 Preparation of the Compound of Compound No. 396

Using 5-chlorosalicylic acid and 3-aminopyridine as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 23.2%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=9.3 Hz), 7.42(1H, ddd, J=9.0, 4.8, 0.6Hz), 7.47(1H, dd, J=8.7, 5.7 Hz), 7.92(1H, d, J=2.7 Hz), 8.15(1H, ddd,J=8.4, 2.4, 1.5 Hz), 8.35(1H, dd, J=7.8, 1.5 Hz), 8.86(1H, d, J=2.4 Hz),10.70(1H, s).

Example 397 Preparation of the Compound of Compound No. 397

Using 5-chlorosalicylic acid and 2-amino-6-bromopyridine as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 12.3%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.42(1H, d, J=7.8 Hz),7.51(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, t, J=7.5 Hz), 7.94(1H, d, J=3.0Hz), 8.24(1H, d, J=7.8 Hz), 10.95(1H, s), 11.97(1H, s).

Example 398 Preparation of the Compound of Compound No. 398 (1)2-Acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide

Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as the rawmaterials, the same operation as the Example 198(3) gave the titlecompound.

Yield: 19.7%.

¹H-NMR(CDCl₃): δ 2.42(3H, s), 7.19(1H, d, J=8.7 Hz), 7.54(1H, dd, J=8.7,2.7 Hz), 8.01(1H, d, J=2.4 Hz), 8.28(1H, dd, J=2.4, 1.8 Hz), 8.42(1H, d,J=2.4 Hz), 9.09(1H, s), 9.66(1H, d, J=1.8 Hz).

(2) 5-Chloro-2-hydroxy-N-(pyridazin-2-yl)benzamide (Compound No. 398)

Using 2-acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide as the rawmaterial, the same operation as the Example 2(2) gave the titlecompound.

Yield: 72.6%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.96(1H, d, J=2.7 Hz), 8.44-8.47(2H, m), 9.49(1H, s), 10.99(1H, s),12.04(1H, s).

Example 399 Preparation of the Compound of Compound No. 399

Using 5-bromosalicylic acid and 2-amino-5-bromopyrimidine as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 10.3%.

¹H-NMR(DMSO-d₆): δ 6.98(1H, d, J=8.8 Hz), 7.59(1H, dd, J=8.8, 2.4 Hz),8.00(1H, d, J=2.8 Hz), 8.86(2H, s), 11.09(1H, s), 11.79(1H, s).

Example 400 Preparation of the Compound of Compound No. 400

Using 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylicacid (Compound No. 394) and propylamine as the raw materials, the sameoperation as the Example 212(2) gave the title compound.

Yield: 23.1%.

¹H-NMR(DMSO-d₆): δ 0.82(3H, t, J=7.5 Hz), 1.39-1.51(2H, m), 3.13(2H, q,J=6.6 Hz), 7.02(1H, d, J=9.0 Hz), 7.40-7.48(3H, m), 7.63(1H, dd, J=8.7,2.7 Hz), 7.68-7.72(2H, m), 8.06(1H, d, J=2.7 Hz), 8.18(1H, t, J=5.7 Hz),11.87(1H, brs), 12.14(1H, brs).

Example 401 Preparation of the Compound of Compound No. 401

Using 5-chlorosalicylic acid and2-methyl-3,5-bis(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 15.0%.

¹H-NMR(DMSO-d₆): δ 2.49(3H, s), 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd,J=8.7, 2.8 Hz), 7.84(1H, s), 7.97(1H, d, J=2.8 Hz), 8.60(1H, s),10.69(1H, brs), 12.07(1H, brs).

Example 402 Preparation of the Compound of Compound No. 402

Using 5-chlorosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 66.5%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.73(1H, d, J=8.7 Hz), 7.86(1H, d, J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4Hz), 8.32(1H, d, J=2.4 Hz), 10.69(1H, s), 11.49(1H, s).

Example 403 Preparation of the Compound of Compound No. 403

Using 5-chlorosalicylic acid and 4-isopropyl-2-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 33.4%.

¹H-NMR(DMSO-d₆): δ 1.24(6H, d, J=6.6 Hz), 2.97-3.06(1H, m), 7.06(1H, d,J=8.7 Hz), 7.51(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s), 7.62(1H, d, J=7.5Hz), 7.98(1H, d, J=2.7 Hz), 8.03(1H, d, J=8.1 Hz), 10.67(1H, s),12.21(1H, s).

Example 404 Preparation of the Compound of Compound No. 404

Using 5-chlorosalicylic acid and 3-(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 68.5%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.6 Hz), 7.46-7.51(2H, m), 7.62(1H, t,J=7.9 Hz), 7.90(1H, d, J=3.0 Hz), 7.94(1H, d, J=9.2 Hz), 8.21(1H, s),10.64(1H, s), 11.58(1H, brs).

Example 405 Preparation of the Compound of Compound No. 405

Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethyl)aniline asthe raw materials the same operation as the Example 16 gave the titlecompound.

Yield: 18.7%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.54(1H, dd, J=8.7, 2.7 Hz),7.94(1H, d, J=2.7 Hz), 8.17(1H, dd, J=9.0, 2.4 Hz), 8.46(1H, d, J=1.8Hz), 8.88(1H, d, J=9.0 Hz), 12.19(1H, s), 12.25(1H, s).

Example 406 Preparation of the Compound of Compound No. 406

Using 5-chlorosalicylic acid and 2,6-dichloro-4-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 22.1%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.55(1H, dd, J=8.7, 2.7 Hz),7.99(1H, d, J=2.4 Hz), 8.10(2H, s), 10.62(1H, s), 11.88(1H, s).

Example 407 Preparation of the Compound of Compound No. 407

Using 5-chlorosalicylic acid and 4-cyano-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 55.8%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.7 Hz),7.80(1H, d, J=2.7 Hz), 8.17(2H, s), 8.43(1H, s), 10.94(1H, s), 11.34(1H,s).

Example 408 Preparation of the Compound of Compound No. 408

Using 5-chlorosalicylic acid and 4-bromo-3-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 81.2%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz),7.85-7.94(3H, m), 8.31(1H, d, J=1.8 Hz), 10.67(1H, s), 11.48(1H, s).

Example 409 Preparation of the Compound of Compound No. 409

Using 5-chlorosalicylic acid and 4-bromo-2-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 41.8%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.7 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz),7.93-7.97(3H, m), 8.21(1H, d, J=9.3 Hz), 10.81(1H, s), 12.28(1H, s).

Example 410 Preparation of the Compound of Compound No. 410

Using 5-chlorosalicylic acid and 2-bromo-4-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 17.6%.

¹H-NMR(DMSO-d₆): δ 7.10(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz),7.82(1H, dd, J=9.0, 1.8 Hz), 7.98(1H, d, J=3.0 Hz), 8.11(1H, d, J=1.5Hz), 8.67(1H, d, J=8.7 Hz), 11.05(1H, s), 12.40(1H, s).

Example 411 Preparation of the Compound of Compound No. 411

Using 5-chlorosalicylic acid and 4-fluoro-2-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 36.0%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=9.0 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.63(1H, td, J=8.7, 3.3 Hz), 7.71(1H, dd, J=8.7, 3.0 Hz), 7.97(1H, d,J=2.7 Hz), 8.11(1H, dd, J=8.7, 5.1 Hz), 10.67(1H, s), 12.20(1H, s).

Example 412 Preparation of the Compound of Compound No. 412

Using 5-chlorosalicylic acid and4-isopropyloxy-2-(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 39.2%.

¹H-NMR(DMSO-d₆): δ 1.29(6H, d, J=5.7 Hz), 4.67-4.79(1H, m), 7.04(1H, d,J=9.0 Hz), 7.22(1H, d, J=2.7 Hz), 7.30(1H, dd, J=8.7, 2.7 Hz), 7.51(1H,dd, J=8.7, 2.4 Hz), 7.86(1H, d, J=9.0 Hz), 7.99(1H, d, J=3.0 Hz),10.50(1H, s), 12.18(1H, s).

Example 413 Preparation of the Compound of Compound No. 413

Using 5-chlorosalicylic acid and2,4-dimethoxy-5-(trifluoromethyl)aniline as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 19.0%.

¹H-NMR(CDCl₃): δ 3.93(3H, s),4.03(3H, s),6.70(1H, s), 6.98(1H, d, J=8.9Hz),7.39(1H, dd, J=8.9, 2.6 Hz), 7.45(1H, d, J=2.6 Hz), 8.29(1H, brs, ),8.54(1H, s), 11.92(1H, s).

Example 414 Preparation of the Compound of Compound No. 414

Using 5-chlorosalicylic acid and 2,4-difluoro-5-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 66.0%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.8 Hz), 7.51(1H, dd, J=8.8, 2.8 Hz),7.82(1H, t, J=10.7 Hz), 7.94(1H, d, J=2.8 Hz), 8.64(1H, d, J=8.0 Hz),10.78(1H, s), 12.37(1H, brs).

Example 415 Preparation of the Compound of Compound No. 415

Using 5-chlorosalicylic acid and 4-cyano-2-(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 24.8%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.8 Hz), 7.52(1H, dd, J=2.8, 8.8 Hz),7.94(1H, d, J=2.8 Hz), 8.17(1H, dd, J=1.8, 8.9 Hz), 8.31(1H, d, J=2.1Hz), 8.63(1H, d, J=8.9 Hz), 11.16(1H, s), 12.45(1H, br.s).

Example 416 Preparation of the Compound of Compound No. 416

Using 5-chlorosalicylic acid and4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 8.5%.

¹H-NMR(CDCl₃): δ 6.98(1H, d, J=8.9 Hz), 7.13(1H, d, J=2.6 Hz), 7.22(2H,d, J=8.6 Hz), 7.34(2H, d, J=8.6 Hz), 7.40(1H, dd, J=2.3, 8.9 Hz),7.66(1H, s), 8.71(1H, s), 8.80(1H, s), 11.42(1H, s).

Example 417 Preparation of the Compound of Compound No. 417

Using 5-chlorosalicylic acid and5-chloro-2-nitro-4-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 22.8%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.8 Hz), 7.55(1H, dd, J=8.8, 2.8 Hz),7.93(1H, d, J=2.8 Hz), 8.52(1H, s), 9.13(1H, s), 12.38(1H, brs),12.45(1H, s).

Example 418 Preparation of the Compound of Compound No. 418

Using 5-chlorosalicylic acid and 2,3-difluoro-4-(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 21.8%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.8 Hz), 7.53(1H, dd, J=2.9, 8.8 Hz),7.66(1H, dt, J=1.8, 7.7 Hz), 7.93(1H, d, J=2.6 Hz), 8.35(1H, t, J=7.7Hz), 11.02(1H, d, J=1.5 Hz), 12.32(1H, s).

Example 419 Preparation of the Compound of Compound No. 419

Using 5-chlorosalicylic acid and4,4′-diamino-2,2′-bis(trifluoromethyl)biphenyl as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 35.9%.

¹H-NMR(DMSO-d₆): δ 7.05(2H, d, J=8.8 Hz), 7.39(2H, d, J=8.5 Hz),7.49-7.51(2H, m), 7.91(2H, d, J=2.5 Hz), 7.99(2H, dd, J=2.0, 8.5 Hz),8.31(2H, d, J=1.9 Hz), 10.71(2H, s), 11.54(2H, s).

Example 420 Preparation of the Compound of Compound No. 420

Using 5-chlorosalicylic acid and2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 42.5%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.8 Hz), 7.53(1H, dd, J=2.9, 8.8 Hz),7.89(1H, d, J=2.6 Hz), 10.65(1H, br.s), 11.76(1H, br.s).

Example 421 Preparation of the Compound of Compound No. 421

Using 5-chlorosalicylic acid and 3′-aminoacetanilide as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 22.4%.

¹H-NMR(DMSO-d₆): δ 2.05(3H, s),7.01(1H, d, J=8.7 Hz),7.24-7.39(3H,m),7.47(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=3.0 Hz), 8.03(1H, s),10.01(1H, s), 10.41(1H, s), 11.87(1H, s).

Example 422 Preparation of the Compound of Compound No. 422 (1)2-Acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide

Using 2-acetoxy-5-chlorobenzoic acid and 3-aminobenzamide as the rawmaterials, the same operation as the Example 24 gave the title compound.

Yield: 15.8%.

¹H-NMR(CDCl₃): δ 2.33(3H, s), 5.89(1H, brs), 6.31(1H, brs), 7.14(1H, d,J=9.0 Hz), 7.42-7.49(2H, m), 7.55-7.58(1H, m), 7.80(1H, d, J=2.7 Hz),7.93(1H, d, J=8.1 Hz), 8.07(1H, s), 8.71(1H, s).

(2) 5-Chloro-2-hydroxy-N-(3-carbamoylphenyl)benzamide (Compound No. 422)

Using 2-acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide as the rawmaterial, the same operation as the Example 2(2) gave the titlecompound.

Yield: 76.0%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.40(1H, brs), 7.45(1H, t,J=7.5 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz), 7.62-7.65(1H, m), 7.86-7.89(1H,m), 7.98-7.99(2H, m), 8.15(1H, t, J=1.8 Hz), 10.51(1H, s), 11.85(1H, s).

Example 423 Preparation of the Compound of Compound No. 423

Using 5-chlorosalicylic acid and 3-amino-N-methylbenzamide as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 19.3%.

¹H-NMR(DMSO-d₆): δ 2.79(3H, d, J=4.5 Hz), 7.03(1H, d, J=9.0 Hz),7.43-7.51(2H, m), 7.59(1H, dt, J=8.1, 1.5 Hz), 7.87(1H, ddd, J=8.1, 2.1,0.9 Hz), 7.99(1H, d, J=2.4 Hz), 8.15(1H, t, J=1.8 Hz), 8.46(1H, d, J=4.2Hz), 10.52(1H, s), 11.84(1H, s).

Example 424 Preparation of the Compound of Compound No. 424

Using 5-chlorosalicylic acid and 2,6-diisopropylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 52.5%.

¹H-NMR(DMSO-d₆): δ 1.14(12H, s), 2.96-3.13(2H, m), 7.16(1H, d, J=8.7Hz), 7.23(1H, d, J=7.5 Hz), 7.33(1H, dd, J=8.4, 6.6 Hz), 7.52(1H, dd,J=8.7, 2.4 Hz), 8.11(1H, d, J=2.4 Hz), 10.09(1H, s), 12.40(1H, s).

Example 425 Preparation of the Compound of Compound No. 425

Using 5-chlorosalicylic acid and 4-methylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 58.6%.

¹H-NMR(DMSO-d₆): δ 2.29(3H, s), 7.01(1H, d, J=8.7 Hz), 7.18(1H, d, J=8.1Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.58(1H, d, J=8.4 Hz), 7.98(1H, d,J=2.7 Hz), 10.35(1H, s), 11.94(1H, s).

Example 426 Preparation of the Compound of Compound No. 426

Using 5-chlorosalicylic acid and 2,6-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 59.6%.

¹H-NMR(DMSO-d₆): δ 2.19(6H, s),7.01(1H, d, J=9.0 Hz), 7.15-7.16(2H, m),7.50(1H, dd, J=9.0, 2.7 Hz), 8.07(1H, d, J=2.7 Hz), 10.03(1H, s),10.10(1H, s), 12.29(1H, s).

Example 427 Preparation of the Compound of Compound No. 427

Using 5-chlorosalicylic acid and 3,4-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 68.3%.

¹H-NMR(DMSO-d₆): δ 2.20(3H, s), 2.23(3H, s), 7.01(1H, d, J=9.0 Hz),7.13(1H, d, J=8.4 Hz), 7.40-7.47(2H, m), 7.47(1H, dd, J=9.0, 2.7 Hz),7.99(1H, d, J=2.7 Hz), 10.29(1H, s), 11.97(1H, brs).

Example 428 Preparation of the Compound of Compound No. 428

Using 5-chlorosalicylic acid and 2,4,6-trimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 61.0%.

¹H-NMR(DMSO-d₆): δ 2.14(6H, s), 2.26(3H, s), 6.95(2H, s), 7.00(1H, d,J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d, J=2.4 Hz), 10.03(1H,s), 12.37(1H, s).

Example 429 Preparation of the Compound of Compound No. 429

Using 5-chlorosalicylic acid and 3-(trifluoromethoxy)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 41.4%.

¹H-NMR(CDCl₃): δ 7.00(1H, d, J=9.0 Hz), 7.09(1H, d, J=7.5 Hz),7.40-7.48(3H, m), 7.51(1H, d, J=2.4 Hz), 7.64(1H, s), 7.94(1H, s),11.66(1H, s).

Example 430 Preparation of the Compound of Compound No. 430

Using 5-chlorosalicylic acid and 2-benzylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 93.3%.

¹H-NMR(CDCl₃): δ 4.08(2H, s), 6.56(1H, d, J=2.5 Hz), 6.92(1H, d, J=8.8Hz), 7.20-7.46(9H, m), 7.53(1H, brs), 7.85(1H, d, J=8.0 Hz), 12.01(1H,brs).

Example 431 Preparation of the Compound of Compound No. 431

Using 5-chlorosalicylic acid and 4-(trifluoromethoxy)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 20.4%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=9.3 Hz), 7.39(2H, d, J=9.0 Hz),7.48(1H, dd, J=9.0, 2.7 Hz), 7.83(2H, d, J=9.3 Hz), 7.92(1H, d, J=2.7Hz), 10.54(1H, s), 11.78(1H, s).

Example 432 Preparation of the Compound of Compound No. 432

Using 5-chlorosalicylic acid and 2,4-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 60.0%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.48-7.54(2H, m), 7.75(1H, d,J=2.1 Hz), 7.98(1H, d, J=2.7 Hz), 8.44(1H, d, J=8.7 Hz), 10.93(1H, s),12.31(1H, s).

Example 433 Preparation of the Compound of Compound No. 433

Using 5-chlorosalicylic acid and 4-(tert-butyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 69.0%.

¹H-NMR(DMSO-d₆): δ 1.29(9H, s), 7.01(1H, d, J=8.7 Hz), 7.39(2H, d, J=8.4Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.61(2H, d, J=8.4 Hz), 7.99(1H, d,J=2.4 Hz), 10.37(1H, s), 11.96(1H, s).

Example 434 Preparation of the Compound of Compound No. 434

Using 5-chlorosalicylic acid and 2,3-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 79.5%.

¹H-NMR(DMSO-d₆): δ 2.14(3H, s),2.29(3H, s), 7.03(1H, d, J=9.0 Hz),7.06-7.15(2H, m), 7.46-7.51(2H, m), 8.05(1H, d, J=3.0 Hz), 10.32(1H, s),12.28(1H, s).

Example 435 Preparation of the Compound of Compound No. 435

Using 5-chlorosalicylic acid and 5-aminoindane as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 80.7%.

¹H-NMR(DMSO-d₆): δ 1.98-2.08(2H, m), 2.81-2.89(4H, m), 7.01(1H, d, J=8.8Hz), 7.21(1H, d, J=8.0, Hz), 7.42(1H, dd, J=8.0, 1.9 Hz), 7.48(1H, dd,J=8.8, 2.8 Hz), 7.60(1H, s), 7.99(1H, d, J=2.8, Hz), 10.34(1H, s),12.00(1H, brs).

Example 436 Preparation of the Compound of Compound No. 436

Using 5-chlorosalicylic acid and 2,4-dimethylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 37.1%.

¹H-NMR(DMSO-d₆): δ 2.23(3H, s), 2.28(3H, s), 7.03(2H, d, J=8.7 Hz),7.10(1H, s), 7.49(1H, dd, J=9.0, 2.7 Hz), 7.63(1H, d, J=8.1 Hz),8.03(1H, d, J=2.4 Hz), 10.24(1H, s), 12.25(1H, s).

Example 437 Preparation of the Compound of Compound No. 437

Using 5-chlorosalicylic acid and 3-isopropyloxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 21.5%.

¹H-NMR(CDCl₃): δ 1.36(6H, d, J=6.0 Hz), 4.52-4.64(1H, m), 6.75(1H, ddd,J=8.4, 2.4, 0.9 Hz), 6.99(1H, d, J=8.7 Hz), 7.03(1H, ddd, J=8.1, 2.1,0.9 Hz), 7.25-7.31(3H, m), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.49(1H, d,J=2.4 Hz), 7.81(1H, s).

Example 438 Preparation of the Compound of Compound No. 438

Using 5-chlorosalicylic acid and 2,6-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 10.3%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 7.8 Hz),7.54(1H, dd, J=9.0, 2.7 Hz), 7.62(1H, d, J=8.1 Hz), 8.05(1H, d, J=2.4Hz), 10.52(1H, s), 12.01(1H, s).

Example 439 Preparation of the Compound of Compound No. 439

Using 5-chlorosalicylic acid and 4-isopropyloxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 76.8%.

¹H-NMR(DMSO-d₆): δ 1.26(6H, d, J=6.3 Hz), 4.52-4.64(1H, m), 6.93(2H, dt,J=9.0, 2.1 Hz), 7.46(1H, dd, J=9.0, 2.7 Hz), 7.58(2H, dt, J=9.0, 2.1Hz), 7.99(1H, d, J=3.0 Hz), 10.36(1H, s), 11.83(1H, brs).

Example 440 Preparation of the Compound of Compound No. 440

Using 5-chlorosalicylic acid and 4-bromo-2-(trifluoromethoxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 59.2%.

¹H-NMR(CDCl₃): δ 7.01(1H, d, J=9.3 Hz), 7.42-7.52(4H, m), 8.23(1H, s),8.31(1H, d, J=9.3 Hz), 11.35(1H, s).

Example 441 Preparation of the Compound of Compound No. 441

Using 5-chlorosalicylic acid and 4-butylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 77.6%

¹H-NMR(CDCl₃): δ 0.89(3H, t, J=6.9 Hz), 1.27-1.36(6H, m), 1.56-1.64(2H,m), 2.61(2H, t, J=7.8 Hz), 6.99(1H, d, J=9.0 Hz), 7.21(2H, d, J=8.7 Hz),7.39(1H, dd, J=9.0, 2.7 Hz), 7.44-7.49(3H, m), 7.80(1H, s), 11.96(1H,s).

Example 442 Preparation of the Compound of Compound No. 442

Using 5-chlorosalicylic acid and 3-methylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 88.3%.

¹H-NMR(CDCl₃): δ 2.38(3H, s), 6.98(1H, d, J=8.8 Hz), 7.03(1H, d, J=7.4Hz), 7.25-7.40(4H, m), 7.48(1H, d, J=2.2 Hz), 7.83(1H, brs), 11.92(1H,brs).

Example 443 Preparation of the Compound of Compound No. 443

Using 5-chlorosalicylic acid and 4-cyclohexylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 90.6%.

¹H-NMR(CDCl₃): δ 1.15-1.47(5H, m), 1.56-1.87(5H, m), 2.40-2.53(2H, m),7.01(1H, d, J=8.8 Hz), 7.21(2H, d, J=8.5 Hz), 7.47(1H, dd, J=8.8, 2.7Hz), 7.60(2H, d, J=8.5H), 8.00(1H, d, J=2.7 Hz), 10.36(1H, s), 11.98(1H,brs).

Example 444 Preparation of the Compound of Compound No. 444

Using 5-chlorosalicylic acid and 4-benzylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 90.3%.

¹H-NMR(DMSO-d₆): δ 3.93(2H, s),7.01(1H, d, J=9.0 Hz),7.16-7.32(7H, m),7.57(1H, dd, J=9.0, 2.7 Hz), 7.61(2H, d, J=8.4 Hz), 7.96(1H, d, J=2.4Hz), 10.37(1H, s).

Example 445 Preparation of the Compound of Compound No. 445

Using 5-chlorosalicylic acid and 2-amino-4,5-dimethoxybenzonitrile asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 52.8%.

¹H-NMR(DMSO-d₆): δ 3.81(3H, s), 3.86(3H, s), 7.08(1H, d, J=8.7 Hz),7.40(1H, s), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.89(1H, s), 7.99(1H, d, J=3.0Hz), 10.93(1H, s), 12.31(1H, s).

Example 446 Preparation of the Compound of Compound No. 446

Using 5-chlorosalicylic acid and 6-amino-1,4-benzodioxane as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 79.7%.

¹H-NMR(DMSO-d₆): δ 4.25(4H, s), 6.86(1H, d, J=8.8 Hz), 7.00(1H, d, J=8.8Hz), 7.12(1H, dd, J=8.8, 2.5 Hz), 7.33(1H, d, J=2.5 Hz), 7.46(1H, dd,J=8.8, 2.5 Hz), 7.97(1H, d, J=2.5 Hz), 10.27(1H, s), 11.96(1H, s).

Example 447 Preparation of the Compound of Compound No. 447

Using 5-chlorosalicylic acid and 2,4-dichloro-5-(isopropyloxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 76.1%.

¹H-NMR(DMSO-d₆): δ 1.35(6H, d, J=6.0 Hz), 4.58-4.66(1H, m), 7.07(1H, d,J=9.0 Hz), 7.51(1H, dd, J=8.7, 3.0 Hz), 7.68(1H, s), 7.98(1H, d, J=3.0Hz), 8.35(1H, s), 10.94(1H, s), 12.34(1H, s).

Example 448 Preparation of the Compound of Compound No. 448

Using 5-chlorosalicylic acid and 4-amino-2-chlorobenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 57.9%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=9.0 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.78(1H, d, J=2.7 Hz), 7.82(1H, dd, J=9.0, 2.1 Hz), 7.97(1H, d, J=8.7Hz), 8.19(1H, d, J=2.1 Hz), 10.79(1H, s), 11.38(1H, s).

Example 449 Preparation of the Compound of Compound No. 449

Using 5-chlorosalicylic acid and 3-chloro-4-(trifluoromethoxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 50.6%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.60(1H, dd, J=9.0, 1.5 Hz), 7.76(1H, dd, J=9.0, 2.4 Hz), 7.85(1H, d,J=3.0 Hz), 8.13(1H, d, J=2.4 Hz), 10.61(1H, s), 11.51(1H, s).

Example 450 Preparation of the Compound of Compound No. 450

Using 5-chlorosalicylic acid and 4-amino-3-methylbenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 80.6%.

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 7.06(1H, d, J=8.7 Hz), 7.49(1H, dd,J=8.7, 2.4 Hz), 7.71(1H, dd, J=8.4, 1.8 Hz), 7.77(1H, s), 7.95(1H, d,J=3.0 Hz), 8.40(1H, d, J=8.4 Hz), 10.76(1H, s), 12.31(1H, brs).

Example 451 Preparation of the Compound of Compound No. 451

Using 5-chlorosalicylic acid and 2,3-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 37.1%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=9.0 Hz), 7.40-7.48(2H, m), 7.52(1H, dd,J=9.0, 2.7 Hz), 7.98(1H, d, J=2.7 Hz), 8.40(1H, dd, J=7.2, 2.4 Hz),11.00(1H, s), 12.32(1H, s).

Example 452 Preparation of the Compound of Compound No. 452

Using 5-chlorosalicylic acid and 2-chloroaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 67.3%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.20(1H, td, J=8.1, 1.8 Hz),7.40(1H, td, J=8.4, 1.8 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.57(1H, dd,J=8.4, 1.8 Hz), 8.00(1H, d, J=2.7 Hz), 8.40(1H, dd, J=8.4, 1.8 Hz),10.89(1H, s), 12.27(1H, s).

Example 453 Preparation of the Compound of Compound No. 453

Using 5-chlorosalicylic acid and 4-isopropyl-3-methylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 21.6%.

¹H-NMR(CDCl₃): δ 1.23(6H, d, J=6.9 Hz), 2.36(3H, s), 3.12(1H, m),6.89(1H, d, J=9.0 Hz), 7.15-7.40(5H, m), 7.48(1H, d, J=2.1 Hz), 7.83(1H,brs).

Example 454 Preparation of the Compound of Compound No. 454

Using 5-chlorosalicylic acid and 2-amino-5-[(1,1-dimethyl)propyl]phenolas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 24.9%.

¹H-NMR(CDCl₃): δ 0.69(3H, t, J=7.5 Hz), 1.28(6H, s), 1.63(2H, q, J=7.5Hz), 6.98(1H, d, J=8.7 Hz), 7.01(1H, d, J=9.0 Hz), 7.06(1H, s), 7.15(1H,dd, =8.4, 2.4 Hz), 7.35(1H, d, J=2.1 Hz), 7.42(1H, dd, J=8.7, 2.4 Hz),7.56(1H, d, J=2.4 Hz), 8.26(1H, s), 11.44(1H, s).

Example 455 Preparation of the Compound of Compound No. 455

Using 5-chlorosalicylic acid and 2-methylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 64.7%.

¹H-NMR(DMSO-d₆): δ 2.28(3H, s), 7.05(1H, d, J=8.7 Hz), 7.13(1H, td,J=7.5, 1.5 Hz), 7.22-7.30(2H, m), 7.50(1H, dd, J=9.0, 2.7 Hz), 7.83(1H,d, J=7.8 Hz), 8.03(1H, d, J=3.0 Hz), 10.32(1H, s), 12.22(1H, s).

Example 456 Preparation of the Compound of Compound No. 456

Using 5-chlorosalicylic acid and 4-butylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 82.1%.

¹H-NMR(DMSO-d₆): δ 0.90(3H, t, J=7.2 Hz), 1.24-1.36(2H, m),1.50-1.60(2H, m), 2.56(2H, t, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.19(2H,d, J=8.7 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.59(2H, d, J=8.4 Hz),7.98(1H, d, J=2.7 Hz), 10.36(1H, s), 11.94(1H, s).

Example 457 Preparation of the Compound of Compound No. 457

Using 5-chlorosalicylic acid and 2-amino-6-chlorobenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 12.7%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.7 Hz), 7.52(1H, d, J=8.1 Hz),7.53(1H, dd, J=9.0, 3.0 Hz), 7.76(1H, t, J=8.7 Hz), 7.95(1H, d, J=3.0Hz), 8.34(1H, d, J=8.4 Hz), 11.17(1H, s), 12.39(1H, s).

Example 458 Preparation of the Compound of Compound No. 458

Using 5-chlorosalicylic acid and 2-amino-5-methylbenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 9.0%.

¹H-NMR(CDCl₃): δ 2.48(3H, s), 7.01(1H, d, J=9.0 Hz), 7.10(1H, dd, J=8.0,0.9 Hz), 7.44(1H, d, J=9.0, 2.4 Hz), 7.56(1H, d, J=8.1 Hz), 7.62(1H, d,J=2.4 Hz), 8.22(1H, s), 8.54(1H, brs), 11.25(1H, brs).

Example 459 Preparation of the Compound of Compound No. 459

Using 5-chlorosalicylic acid and 4-benzyloxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 26.8%.

¹H-NMR(DMSO-d₆): δ 5.11(2H, s), 6.99-7.05(3H, m), 7.33-7.49(6H, m),7.60(2H, d, J=9.0 Hz), 7.99(1H, d, J=2.7 Hz), 10.33(1H, s), 12.02(1H,s).

Example 460 Preparation of the Compound of Compound No. 460

Using 5-chlorosalicylic acid and 4-amino-2,2-difluorobenzo[1,3]dioxoleas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 66.9%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, d, J=8.8 Hz), 7.31-7.32(2H, m), 7.51(1H, dd,J=8.8, 2.8 Hz), 7.70(1H, dd, J=5.6, 3.8 Hz), 7.96(1H, d, J=2.8 Hz),10.59(1H, s), 12.05(1H, brs).

Example 461 Preparation of the Compound of Compound No. 461

Using 5-chlorosalicylic acid and5-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxene as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 67.9%.

¹H-NMR(CDCl₃): δ 6.99-7.03(2H, m), 7.21-7.27(2H, m), 7.45(1H, dd, J=8.9,2.5 Hz), 7.52(1H, d, J=2.5 Hz), 8.13(1H, s), 11.44(1H, s).

Example 462 Preparation of the Compound of Compound No. 462

Using 5-chlorosalicylic acid and3-chloro-4-(trifluoromethyl)sulfanylaniline as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 52.3%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.8 Hz), 7.47(1H, dd, J=2.9, 8.8 Hz),7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H, d, J=2.6 Hz), 7.88(1H, d, J=8.8Hz), 8.20(1H, d, J=2.2 Hz), 10.70(1H, s), 11.43(1H, s).

Example 463 Preparation of the Compound of Compound No. 463

Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethoxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 68.4%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=8.8 Hz), 7.52(1H, dd, J=2.6, 8.8 Hz),7.85-7.89(1H, m), 7.93(1H, d, J=2.6 Hz), 8.17(1H, d, J=2.9 Hz), 8.67(1H,d, J=9.5 Hz), 11.92(1H, s), 12.14(1H, s).

Example 464 Preparation of the Compound of Compound No. 464

Using 5-chlorosalicylic acid and 5-amino-2,2-difluorobenzo[1,3]dioxoleas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 75.8%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.8 Hz), 7.42-7.43(2H, m), 7.48(1H, dd,J=8.8, 2.5 Hz), 7.90(1H, d, J=2.5 Hz), 10.54(1H, s), 11.69(1H, s).

Example 465 Preparation of the Compound of Compound No. 465

Using 5-chlorosalicylic acid and 3-benzylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 66.4%.

¹H-NMR(CDCl₃): δ 3.99(2H, s), 6.97(1H, d, J=9.1 Hz), 7.06(1H, d, J=7.4Hz), 7.18-7.48(8H, m), 7.37(1H, dd, J=9.1, 2.5 Hz), 7.45(1H, d, J=2.5Hz), 7.80(1H, brs), 11.88(1H, s).

Example 466 Preparation of the Compound of Compound No. 466

Using 5-chlorosalicylic acid and 2-nitro-4-(trifluoromethoxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 40.9%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 7.05(1H, d, J=8.8 Hz), 7.25(1H, dd,J=1.8, 8.8 Hz), 7.33(1H, d, J=1.8 Hz), 7.49(1H, dd, J=2.9, 8.8 Hz),7.97-8.00(2H, m), 10.37(1H, s), 12.15(1H, s).

Example 467 Preparation of the Compound of Compound No. 467

Using 5-chlorosalicylic acid and 2,3,5-trifluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 54.2%.

¹H-NMR(DMSO-d₆): δ 7.06(1H, d, J=8.8 Hz), 7.28-7.37(1H, m), 7.51(1H, dd,J=2.6, 8.8 Hz), 7.92(1H, d, J=2.6 Hz), 7.98-8.04(1H, m), 10.93(1H, s),12.27(1H, br.s)

Example 468 Preparation of the Compound of Compound No. 468

Using 5-chlorosalicylic acid and 4′-aminobenzo-15-crown-5 as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 45.1%.

¹H-NMR(CDCl₃): δ 3.74-3.77(8H, m), 3.90-3.92(4H, m), 4.10-4.15(4H, m),6.83(1H, d, J=8.5 Hz), 6.96-6.99(2H, m), 7.24(1H, d, J=2.5 Hz), 7.36(1H,dd, J=2.5, 8.8 Hz), 7.53(1H, s), 8.06(1H, br.s), 11.92(1H, s).

Example 469 Preparation of the Compound of Compound No. 469

Using 5-chlorosalicylic acid and 4-bromo-2-fluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 45.1%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, d, J=8.8 Hz), 7.43-7.53(2H, m),7.64-7.71(1H, m), 7.94(1H, d, J=1.5 Hz), 8.20(1H, dd, J=8.4, 8.8 Hz),10.70(1H, s), 12.16(1H, s).

Example 470 Preparation of the Compound of Compound No. 470

Using 5-chlorosalicylic acid and 2,4-bis(methanesulfonyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 7.2%.

¹H-NMR(CDCl₃): δ 3.13(3H, s), 3.21(3H, s), 7.04(1H, d, J=8.9 Hz),7.48(1H, dd, J=2.2, 8.9 Hz), 7.62(1H, d, J=2.2 Hz), 8.24(1H, dd, J=2.4,9.0 Hz), 8.56(1H, d, J=2.4 Hz), 8.91(1H, d, J=8.9 Hz), 10.96(1H, s),11.57(1H, s).

Example 471 Preparation of the Compound of Compound No. 471

A mixture of 5-chlorosalicylic acid (87 mg, 0.5 mmol),2,2-bis(3-amino-4-methylphenyl)-1,1,1,3,3,3-hexafluoropropane (363 mg, 1mmol), phosphorus trichloride (44 μL, 0.5 mmol) and toluene (4 mL) wasrefluxed for 4 hours. After the reaction mixture was cooled to roomtemperature, it was purified by column chromatography on silicagel(n-hexane:ethyl acetate=5:1) to give the white title compound (16 mg,4.9%). (The compound of Compound No. 529 described in the followingExample 529 was obtained as a by-product.)

¹H-NMR(DMSO-d₆): δ 2.34(6H, s), 7.04(4H, d, J=8.8 Hz), 7.39(2H, d, J=8.4Hz), 7.48(2H, dd, J=2.9, 8.8 Hz), 7.96(2H, d, J=2.9 Hz), 8.19(2H, s),10.44(2H, s), 12.17(2H, s).

Example 472 Preparation of the Compound of Compound No. 472

Using 5-chlorosalicylic acid and6-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo-[1,4]dioxene as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 10.1%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.8 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz),7.50(1H, d, J=9.0 Hz), 7.59(1H, dd, J=8.8, 2.2 Hz), 7.86(1H, d, J=2.7Hz), 7.92(1H, d, J=2.2 Hz), 10.59(1H, s), 11.55(1H, s).

Example 473 Preparation of the Compound of Compound No. 473

Using 5-chlorosalicylic acid and 2-amino-5-chlorobenzophenone as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 27.6%.

¹H-NMR(DMSO-d₆): δ 6.96(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 3.0 Hz),7.49-7.56(3H, m), 7.64-7.75(5H, m), 8.21(1H, d, J=9.3 Hz), 11.21(1H, s),11.83(1H, s).

Example 474 Preparation of the Compound of Compound No. 474

Using 5-chlorosalicylic acid and 2-bromo-4-fluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 77.1%.

¹H-NMR(DMSO-d₆): δ 7.07(1H, d, J=9.0 Hz), 7.31-7.38(1H, m), 7.51(1H, dd,J=9.0, 3.0 Hz), 7.72(1H, d, J=8.1, 3.0 Hz), 8.00(1H, d, J=3.0 Hz),8.23(1H, dd, J=9.3, 5.4 Hz), 10.70(1H, s), 12.24(1H, s).

Example 475 Preparation of the Compound of Compound No. 475

Using 5-chlorosalicylic acid and 4-hexyloxyaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 74.8%.

¹H-NMR(DMSO-d₆): δ 0.88(3H, t, J=6.6 Hz), 1.28-1.46(6H, m),2.49-2.52(2H, m), 3.95(2H, t, J=6.6 Hz), 6.91-6.96(2H, m), 7.00(1H, d,J=8.8 Hz), 7.46(1H, dd, J=8.8, 2.9 Hz), 7.55-7.61(2H, m), 8.00(1H, d,J=2.9 Hz), 10.31(1H, 9), 12.03(1H, s).

Example 476 Preparation of the Compound of Compound No. 476

Using 5-chlorosalicylic acid and2,2-bis(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropane as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 64.5%.

¹H-NMR(DMSO-d₆): δ 6.99(2H, d, J=8.8 Hz), 7.11(2H, d, J=8.0 Hz),7.45(2H, dd, J=8.8, 2.6 Hz), 7.50(2H, t, J=8.4 Hz), 7.86(2H, d, J=2, 6Hz), 7.88-7.91(4H, m), 10.53(2H, s), 11.56(2H, s).

Example 477 Preparation of the Compound of Compound No. 477

Using 5-chlorosalicylic acid and 2,4,5-trichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 38.9%.

¹H-NMR(CDCl₃): δ 7.02(1H, d, J=8.6 Hz),7.46(1H, d, J=8.6 Hz), 7.49(1H,s),7.57(1H, s), 8.41(1H, br.s), 8.63(1H, s), 11.42(1H, s).

Example 478 Preparation of the Compound of Compound No. 478

Using 5-chlorosalicylic acid and 3-isopropylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 55.3%.

¹H-NMR(DMSO-d₆): δ 1.22(6H, d, 6.9 Hz), 2.76-2.94(1H, m), 7.01(1H, d,J=8.6 Hz), 7.04(1H, d, J=7.9 Hz), 7.29(1H, t, J=7.9 Hz), 7.47(1H, dd,J=8.6, 2.6 Hz), 7.54(1H, d, J=7.9 Hz), 7.57(1H, s), 7.98(1H, d, J=2.6Hz), 10.37(1H, s), 11.90(1H, brs).

Example 479 Preparation of the Compound of Compound No. 479

Using 5-chlorosalicylic acid and 4-aminobenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 45.6%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz),7.83(1H, d, J=2.6 Hz), 7.84(2H, d, J=8.9 Hz), 7.92(2H, d, J=8.9 Hz),10.71(1H, s), 11.59(1H, brs).

Example 480 Preparation of the Compound of Compound No. 480

Using 5-chlorosalicylic acid and 3-aminobenzonitrile as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 97.1%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz),7.56-7.63(2H, m), 7.88(1H, d, J=2.7 Hz), 7.95-8.02(1H, m), 8.20-8.21(1H,m), 10.62(1H, s), 11.57(1H, s).

Example 481 Preparation of the Compound of Compound No. 481

Using 5-chlorosalicylic acid and 3,4-dimethoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 73.3%.

¹H-NMR(DMSO-d₆): δ 3.75(3H, s), 3.76(3H, s), 6.95(1H, d, J=8.7 Hz),7.01(1H, d, J=9.0 Hz), 7.24(1H, dd, J=8.7, 2.7 Hz), 7.38(1H, d, J=2.1Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 8.00(1H, d, J=2.4 Hz), 10.30(1H, s),12.01(1H, s).

Example 482 Preparation of the Compound of Compound No. 482

Using 5-chlorosalicylic acid and 4-aminophenylacetic acid ethyl ester asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 66.1%.

¹H-NMR(DMSO-d₆): δ 1.19(3H, t, J=7.5 Hz), 3.64(2H, s), 4.08(2H, q, J=7.2Hz), 7.01(1H, d, J=8.7 Hz), 7.26(2H, d, J=8.7 Hz), 7.47(1H, dd, J=8.7,3.0 Hz), 7.64(1H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 10.40(1H, s),11.87(1H, s).

Example 483 Preparation of the Compound of Compound No. 483

Using 5-chlorosalicylic acid and 3-[(trifluoromethyl)sulfanyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 67.1%.

¹H-NMR(CDCl₃): δ 7.01(1H, d, J=8.9 Hz), 7.42(1H, dd, J=8.9, 2.3 Hz),7.47-7.53(2H, m), 7.51(1H, d, J=2.3 Hz), 7.76(1H, dt, J=7.6 Hz, 2.0 Hz),7.88(1H, brs), 7.92(1H, s), 11.64(1H, s).

Example 484 Preparation of the Compound of Compound No. 484

Using 5-chlorosalicylic acid and 4-[(trifluoromethyl)sulfanyl]aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 63.2%.

¹H-NMR(CDCl₃): δ 7.01(1H, d, J=8.9 Hz), 7.43(1H, dd, J=8.9, 2.3 Hz),7.50(1H, d, J=2.3 Hz), 7.70(4H, s), 7.90(1H, brs), 11.60(1H, s).

Example 485 Preparation of the Compound of Compound No. 485

Using 5-chlorosalicylic acid and 4-(trifluoromethanesulfonyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 38.7%.

¹H-NMR(DMSO-d₆): δ 7.04(1H, d, J=8.6 Hz), 7.49(1H, dd, J=8.6, 2.6 Hz),7.80(1H, d, J=2.6 Hz), 8.12(2H, d, J=9.4 Hz), 8.17(2H, d, J=9.4 Hz),8.16(1H, s), 10.95(1H, s), 11.37(1H, brs).

Example 486 Preparation of the Compound of Compound No. 486

Using 5-chlorosalicylic acid and 3,4-difluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 75.4%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.9 Hz), 7.39-7.51(3H, m),7.85-7.93(2H, m), 10.51, (1H, s), 11.60(1H, s).

Example 487 Preparation of the Compound of Compound No. 487

Using 5-chlorosalicylic acid and 3-ethynylaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 35.8%.

¹H-NMR(DMSO-d₆): δ 4.22(1H, s), 7.02(1H, d, J=8.6 Hz), 7.25(1H, d, J=7.6Hz), 7.39(1H, t, J=7.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.70(1H, d,J=7.6 Hz), 7.89(1H, s), 7.91(1H, d, J=2.6 Hz), 10.46(1H, s), 11.69(1H,brs).

Example 488 Preparation of the Compound of Compound No. 488

Using 5-chlorosalicylic acid and 4-(sec-butyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 40.1%.

¹H-NMR(DMSO-d₆): δ 0.77(3H, t, 7.4 Hz), 1.19(3H, d, 6.9 Hz),1.50-1.61(2H, m), 2.52-2.62(1H, m), 7.01(1H, d, J=8.9 Hz), 7.20(2H, d,J=8.6 Hz), 7.47(1H, dd, J=8.9, 2.6 Hz), 7.60(2H, d, J=8.6 Hz), 7.98(1H,d, J=2.6 Hz), 10.36(1H, s), 11.94(1H, brs).

Example 489 Preparation of the Compound of Compound No. 489

Using 5-chlorosalicylic acid and 3-chloro-4-methoxyaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 75.7%.

¹H-NMR(CDCl₃): δ 6.98(2H, t, J=9.2 Hz), 7.38-7.44(2H, m), 7.47(1H, d,J=2.6 Hz), 7.66(1H, d, J=2.6 Hz), 7.73(1H, br.s), 11.81(1H, s).

Example 490 Preparation of the Compound of Compound No. 490

Using 5-chlorosalicylic acid and 3-aminobenzophenone as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 34.3%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.6 Hz), 7.48(1H, dd, J=9.1, 2.6 Hz),7.52-7.62(4H, m), 7.68-7.79(3H, m), 7.93(1H, d, J=2.6 Hz), 8.02(1H, d,J=7.9 Hz), 8.16(1H, s), 10.60(1H, s), 11.68(1H, brs).

Example 491 Preparation of the Compound of Compound No. 491

Using 5-chlorosalicylic acid and 3-methoxyaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 23.5%.

¹H-NMR(DMSO-d₆): δ 3.76(3H, s), 6.69-6.75(1H, m), 7.01(1H, d, J=8.6 Hz),7.25-7.28(2H, m), 7.39(1H, s), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.94(1H, d,J=2.6 Hz), 10.39(1H, s), 11.81(1H, brs).

Example 492 Preparation of the Compound of Compound No. 492

Using 5-chlorosalicylic acid and 4′-aminoacetanilide as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 36.2%.

¹H-NMR(DMSO-d₆): δ 2.50(3H, s), 7.01(1H, d, J=8.6 Hz), 7.47(1H, dd,J=8.6, 2.6 Hz), 7.57(2H, d, J=9.1 Hz), 7.61(2H, d, J=9.1 Hz), 7.98(1H,d, J=2.6 Hz), 9.95(1H, s), 10.38(1H, s), 11.99(1H, brs).

Example 493 Preparation of the Compound of Compound No. 493

Using 5-chlorosalicylic acid and sulfanilamide as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 25.7%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.9 Hz), 7.31(2H, s), 7.47(1H, dd,J=8.9, 2.3 Hz), 7.81(2H, d, J=8.9 Hz), 7.89(2H, d, J=8.9 Hz), 7.89(1H,d, J=2.3 Hz), 10.70(1H, s), 11.55(1H, brs).

Example 494 Preparation of the Compound of Compound No. 494

Using 5-chlorosalicylic acid and2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as the rawmaterials, the same operation as the Example 16 gave the title compound.(The compound was obtained by separation from the mixture with thecompound of Compound No. 498 described in the following Example 498.)

Yield: 11.7%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz),7.68(2H, d, J=8.7 Hz), 7.85(2H, d, J=8.7 Hz), 7.91(1H, d, J=2.6 Hz),8.69(1H, s), 10.62(1H, s).

Example 495 Preparation of the Compound of Compound No. 495

Using 5-chlorosalicylic acid and 2-chloro-4-nitroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 39.6%.

¹H-NMR(CDCl₃): δ 7.04(1H, d, J=8.9 Hz), 7.47(1H, dd, J=2.3, 8.9 Hz),7.54(1H, d, J=2.3 Hz), 8.25(1H, dd, J=2.6, 8.9 Hz), 8.39(1H, d, J=2.3Hz), 8.73(1H, d, J=9.2 Hz), 8.76(1H, br.s), 11.22(1H, s).

Example 496 Preparation of the Compound of Compound No. 496

Using 5-chlorosalicylic acid and 2,4-difluoroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 67.8%.

¹H-NMR(DMSO-d₆): δ 7.05(1H, dd, J=1.7, 8.9 Hz), 7.15(1H, dt, J=1.7, 9.2Hz), 7.41(1H, ddd, J=2.3, 8.9, 9.2 Hz), 7.51(1H, dt, J=2.3, 8.9 Hz),7.98(1H, d, J=2.3 Hz), 8.11(1H, dd, J=8.9, 15.1 Hz), 10.59(1H, s),12.13(1H, s).

Example 497 Preparation of the Compound of Compound No. 497

Using 5-chlorosalicylic acid and 4-(difluoromethoxy)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 85.9%.

¹H-NMR(DMSO-d₆): δ 7.01(1H, d, J=8.6 Hz), 7.19(1H, t, J=74.2 Hz),7.20(2H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.74(2H, d, J=8.9Hz), 7.94(1H, d, J=2.6 Hz), 10.47(1H, s), 11.80(1H, brs).

Example 498 Preparation of the Compound of Compound No. 498

This compound was obtained by separation from the mixture with thecompound of Compound No. 494 described in the aforementioned Example494.

Yield: 11.6%.

¹H-NMR(DMSO-d₆): δ 7.02(1H, d, J=8.6 Hz), 7.46(1H, dd, J=8.6, 2.3 Hz),7.83(2H, d, J=8.1 Hz), 7.88(1H, d, J=2.3 Hz), 7.95(2H, d, J=8.1 Hz),10.71(1H, s).

Example 499 Preparation of the Compound of Compound No. 499

Using 5-chlorosalicylic acid and 3-(methylsulfanyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 67.2%.

¹H-NMR(DMSO-d₆): δ 2.49(3H, s), 7.00-7.05(1H, m), 7.01(1H, d, J=8.9 Hz),7.31(1H, t, J=7.9 Hz), 7.46(1H, dd, J=8.9, 2.6 Hz), 7.44-7.49(1H, m),7.68(1H, d, J=1.7 Hz), 7.93(1H, d, J=2.6 Hz), 10.47(1H, s).

Example 500 Preparation of the Compound of Compound No. 500

Using 5-chlorosalicylic acid and 4-methanesulfonylaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 28.6%.

¹H-NMR(DMSO-d₆): δ 3.20(3H, s), 7.03(1H, d, J=8.3 Hz), 7.48(1H, dd,J=8.3, 2.6 Hz), 7.87(1H, d, J=2.6 Hz), 7.92(2H, d, J=8.9 Hz), 7.98(2H,d, J=8.9 Hz), 10.75(1H, s), 11.45(1H, brs).

Example 501 Preparation of the Compound of Compound No. 501

Using 5-chlorosalicylic acid and 2-amino-4-methylbenzophenone as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 8.7%.

¹H-NMR(CDCl₃): δ 2.50(3H, s), 6.98(1H, d, J=8.3 Hz), 6.99(1H, d, J=7.3Hz), 7.39(1H, dd, J=2.0, 8.6 Hz), 7.48-7.64(4H, m), 7.72(2H, d, J=7.6Hz), 7.83(1H, d, J=2.3 Hz), 8.57(1H, s), 12.18(1H, s), 12.34(1H, br.s).

Example 502 Preparation of the Compound of Compound No. 502

Using 5-chlorosalicylic acid and 3-amino-N-butylbenzenesulfonamide asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 46.7%.

¹H-NMR(DMSO-d₆): δ 0.80(3H, t, J=7.3 Hz), 1.17-1.41(4H, m),2.73-2.80(2H, m), 7.03(1H, d, J=8.9 Hz), 7.48(1H, dd, J=8.9, 2.0 Hz),7.53-7.64(2H, m), 7.87-7.92(1H, m), 7.92(1H, d, J=2.0 Hz), 8.27(1H, s),10.62(1H, s), 11.63(1H, s).

Example 503 Preparation of the Compound of Compound No. 503

Using 5-chlorosalicylic acid and 3-(benzyloxy)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 68.5%.

¹H-NMR(DMSO-d₆): δ 5.11(2H, s), 6.79-6.83(1H, m), 7.01(1H, d, J=8.9 Hz),7.27-7.49(9H, m), 7.93(1H, d, J=3.0 Hz), 10.40(1H, s), 11.79(1H, brs).

Example 504 Preparation of the Compound of Compound No. 504

Using 5-chlorosalicylic acid andN-(4-aminophenyl)-4-methylbenzenesulfonamide as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 40.6%.

¹H-NMR(DMSO-d₆): δ 2.33(3H, s), 6.99(1H, d, J=8.6 Hz), 7.07(2H, d, J=8.6Hz), 7.34(2H, d, J=8.3 Hz), 7.45(1H, dd, J=8.6, 2.1 Hz), 7.53(2H, d,J=8.6 Hz), 7.63(2H, d, J=8.3 Hz), 7.90(1H, d, J=2.1 Hz), 10.14(1H, s),10.33(1H, s), 11.81(1H, brs).

Example 505 Preparation of the Compound of Compound No. 505

Using 5-chlorosalicylic acid and 4-(morpholino)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 29.8%.

¹H-NMR(DMSO-d₆): δ 3.09(4H, t, J=4.6 Hz), 3.74(4H, t, J=4.6 Hz),6.94-7.01(3H, m), 7.46(1H, dd, J=8.9, 2.6 Hz), 7.55(2H, d, J=8.9 Hz),8.01(1H, d, J=2.6 Hz), 10.29(1H, s), 12.10(1H, brs).

Example 506 Preparation of the Compound of Compound No. 506

Using 5-chlorosalicylic acid and 3-(tert-butyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 76.1%.

¹H-NMR(CDCl₃): 5 1.35(9H, s), 6.99(1H, d, J=8.9 Hz), 7.24-7.28(1H, m),7.32-7.35(1H, m), 7.40(1H, dd, J=8.9, 2.3 Hz), 7.46-7.50(2H, m),7.51(1H, d, J=2.3 Hz), 7.81(1H, brs), 11.94(1H, s).

Example 507 Preparation of the Compound of Compound No. 507

Using 5-chlorosalicylic acid and 3-(5-methylfuran-2-yl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 61.1%.

¹H-NMR(DMSO-d₆): δ 2.36(3H, s), 6.22-6.23(1H, m), 6.81(1H, d, J=3.0 Hz),7.02(1H, d, J=8.9 Hz), 7.36-7.51(3H, m), 7.58-7.61(1H, m), 7.99-8.01(2H,m), 10.49(1H, s), 11.85(1H, brs).

Example 508 Preparation of the Compound of Compound No. 508

Using 5-chlorosalicylic acid and 3-(1-hydroxyethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 37.6%.

¹H-NMR(DMSO-d₆): δ 1.80(3H, d, J=6.6 Hz), 5.33(1H, q, J=6.6 Hz),7.01(1H, d, J=8.9 Hz), 7.25(1H, d, J=7.9 Hz), 7.38(1H, t, J=7.9 Hz),7.47(1H, dd, J=8.9, 2.3 Hz), 7.65(1H, d, J=7.9 Hz), 7.85(1H, s),7.96(1H, d, J=2.3 Hz), 10.48(1H, s), 11.80(1H, brs).

Example 509 Preparation of the Compound of Compound No. 509

Using 5-chlorosalicylic acid and 3-aminobenzenesulfonamide as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 18.7%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.9 Hz), 7.41(2H, s), 7.48(1H, dd,J=8.9, 2.6 Hz), 7.54-7.62(2H, m), 7.84-7.88(1H, m), 7.93(1H, d, J=2.6Hz), 8.30(1H, s), 10.64(1H, s), 11.68(1H, brs).

Example 510 Preparation of the Compound of Compound No. 510

Using 5-chlorosalicylic acid and 3-(trifluoromethanesulfonyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 62.6%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.6 Hz), 7.48(1H, dd, J=8.6, 2.6 Hz),7.82-7.88(3H, m), 8.23-8.26(1H, m), 8.67(1H, s), 10.88(1H, s), 11.45(1H,brs).

Example 511 Preparation of the Compound of Compound No. 511

Using 5-chlorosalicylic acid and 2-bromo-4-(trifluoromethoxy)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 17.1%.

¹H-NMR(CDCl₃): δ 7.02(1H, d, J=8.9 Hz),7.26-7.31(1H, m), 7.44(1H, dd,J=8.9,2.6 Hz), 7.53(2H, d, J=2.6 Hz), 8.41(1H, brs, ), 8.42(1H, d, J=8.9Hz), 11.57(1H, s).

Example 512 Preparation of the Compound of Compound No. 512

Using 5-chlorosalicylic acid and 3,4-(dihexyloxy)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 60.5%.

¹H-NMR(CDCl₃): δ 0.91(6H, t, J=6.3 Hz), 1.34-1.61(12H, m), 1.76-1.89(4H,m), 3.97-4.04(4H, m), 6.88(1H, d, J=8.9 Hz), 6.97-7.00(2H, m), 7.22(1H,d, J=2.6 Hz), 7.38(1H, dd, J=8.9, 2.6 Hz), 7.47(1H, d, J=2.6 Hz),7.73(1H, s), 11.97(1H, s).

Example 513 Preparation of the Compound of Compound No. 513

Using 5-chlorosalicylic acid and 3,4-dichloroaniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 16.4%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 77.47(1H, dd, J=8.7, 2.7 Hz),7.61-7.70(2H, m), 7.86(1H, d, J=2.7 Hz), 8.11(1H, d, J=2.1 Hz),10.56(1H, s), 11.53(1H, s).

Example 514 Preparation of the Compound of Compound No. 514

Using 5-chlorosalicylic acid and 3-hexyloxyaniline as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 88.2%.

¹H-NMR(DMSO-d₆): δ 0.89(3H, t, J=7.0 Hz), 1.28-1.47(6H, m),1.67-1.76(2H, m), 3.95(2H, t, J=6.6 Hz), 6.69-6.73(1H, m), 7.01(1H, d,J=8.8 Hz), 7.21-7.28(2H, m), 7.39-7.40(1H, m), 7.67(1H, dd, J=8.8, 2.6Hz), 7.94(1H, d, J=2.6 Hz), 10.34(1H, s), 11.80(1H, s).

Example 515 Preparation of the Compound of Compound No. 515

Using 5-chlorosalicylic acid and 5-ethoxy-4-fluoro-2-nitroaniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 20.2%.

¹H-NMR(DMSO-d₆): δ 1.43(3H, t, J=7.0 Hz), 4.27(2H, q, J=7.0 Hz),7.07(1H, d, J=8.8 Hz), 7.52(1H, dd, J=8.8, 2.9 Hz), 7.95(1H, d, J=2.9Hz), 8.15(1H, d, J=11.4 Hz), 8.57(1H, d, J=8.4 Hz), 12.16(1H, s),12.26(1H, s).

Example 516 Preparation of the Compound of Compound No. 516

Using 5-chlorosalicylic acid and 4-hydroxy-3-methyl-1-naphthylamine asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 5.9%.

¹H-NMR(DMSO-d₆): δ 2.38(3H, s), 7.03(1H, d, J=9.3 Hz), 7.43(2H, s),7.46(1H, d, J=2.4 Hz), 7.50-7.54(2H, m), 7.67(1H, d, J=2.1 Hz), 7.78(1H,dd, J=6.0, 2.7 Hz), 8.03(1H, brs), 8.18(1H, dd, J=6.0, 3.6 Hz),11.98(1H, brs).

Example 517 Preparation of the Compound of Compound No. 517

This compound is a known compound.

Reference which describes the preparation method: the pamphlet ofInternational Publication WO99/65449.

Example 518 Preparation of the Compound of Compound No. 518

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 519 Preparation of the Compound of Compound No. 519

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 520 Preparation of the Compound of Compound No. 520

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 521 Preparation of the Compound of Compound No. 521

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 522 Preparation of the Compound of Compound No. 522

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 523 Preparation of the Compound of Compound No. 523

This compound is a known compound.

-   Reference which describes the preparation method: the pamphlet of    International Publication WO99/65449.

Example 524 Preparation of the Compound of Compound No. 524

Using 5-chlorosalicylic acid and 4-aminobiphenyl as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 52.4%.

¹H-NMR(DMSO-d₆): δ 7.03(1H, d, J=8.7 Hz), 7.33-7.38(1H, m),7.44-7.51(3H, m), 7.67-7.72(4H, m), 7.82(2H, d, J=8.7 Hz), 7.98(1H, d,J=2.4 Hz), 10.49(1H, s), 11.84(1H, s).

Example 525 Preparation of the Compound of Compound No. 525

A mixture of 5-sulfosalicylic acid (218 mg, 1 mmol),3,5-bis(trifluoromethyl)aniline (229 mg, 1 mmol), phosphorus trichloride(88 μL, 1 mmol) and o-xylene (5 mL) was refluxed for 3 hours. After thereaction mixture was cooled to room temperature, it was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=3:1) to givethe title compound (29 mg, 9.2%) as a white solid.

¹H-NMR(DMSO-d₆): δ 7.15(1H, d, J=8.8 Hz), 7.65(2H, s), 7.73(1H, s),7.81(1H, s), 7.82(1H, dd, J=8.7, 2.5 Hz), 8.23(1H, d, J=2.5 Hz),8.38(2H, s), 10.87(1H, s), 11.15(1H, brs).

Example 526 Preparation of the Compound of Compound No. 526

Using 5-chlorosalicylic acid and 2,4-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 6.9%.

¹H-NMR(CDCl₃): δ 7.03(1H, dd, J=8.7,0.6 Hz), 7.43-7.48(2H, m), 7.91(1H,d, J=9.0 Hz), 7.96(1H, s), 8.42(1H, s), 8.49(1H, d, J=8.7 Hz), 11.26(1H,s).

Example 527 Preparation of the Compound of Compound No. 527

Using 3-phenylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 64.6%.

¹H-NMR(DMSO-d₆): δ 7.12(1H, t, J=8.1 Hz), 7.37(1H, tt, J=7.5, 1.5 Hz),7.43-7.48(2H, m), 7.56-7.60(3H, m), 7.91(1H, s), 8.07, (1H, dd, J=8.1,1.5 Hz), 8.48(2H, s), 11.00(1H, s), 12.16(1H, s).

Example 528 Preparation of the Compound of Compound No. 528

Using 4-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as theraw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 65.7%.

¹H-NMR(DMSO-d₆): δ 6.81-6.90(2H, m), 7.84(1H, s, ), 7.93-7.98(1H, m,),8.45(2H, s, ), 10.78(1H, s), 11.81(1H, s,).

Example 529 Preparation of the Compound of Compound No. 529

This compound was obtained by separation from the mixture with thecompound of Compound No. 471 described in the aforementioned Example471.

Yield: 9.4%.

¹H-NMR(CD₃OD): δ 2.16(3H, s), 2.34(3H, s), 6.69(1H, d, J=8.2 Hz),6.76(1H, brs)6.95(1H, d, J=8.8 Hz), 7.02(1H, d, J=8.0 Hz), 7.15(1H, d,J=8.2 Hz), 7.29(1H, d, J=8.2 Hz), 7.37(1H, dd, J=8.8, 2.6 Hz), 7.97(1H,d, J=2.6 Hz), 7.98(1H, s).

Example 530 Preparation of the Compound of Compound No. 530

Using 5-chlorosalicylic acid and4-amino-3-(trifluoromethoxy)benzonitrile as the raw materials, the sameoperation as the Example 16 gave the title compound.

Yield: 75.2%.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=8.8 Hz), 7.54(1H, dd, J=8.8, 2.6 Hz),7.94(1H, dd, J=8.4, 1.6 Hz), 7.95(1H, d, J=2.6 Hz), 8.15(1H, t, J=1.5Hz), 8.75(1H, d, J=8.8 Hz), 11.25(1H, s), 12.45(1H, s).

Example 531 Preparation of the Compound of Compound No. 531

Using 5-chlorosalicylic acid and4-[2-amino-4-(trifluromethyl)phenoxy]benzonitrile as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 11.6%.

¹H-NMR(CD₃OD): δ 6.88(1H, d, J=8.6 Hz), 7.19(2H, d, J=8.9 Hz), 7.24(1H,d, J=8.6 Hz), 7.33(1H, dd, J=8.8, 2.8 Hz), 7.46(1H, dd, J=8.9, 1.9 Hz),7.76(2H, d, J=8.9 Hz), 7.98(1H, d, J=2.7 Hz), 8.96(1H, s).

Example 532 Preparation of the Compound of Compound No. 532

Using 5-chlorosalicylic acid and3-amino-4-(4-methoxyphenoxy)-benzotrifluoride as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 88.1%.

¹H-NMR(CDCl₃): δ 3.85(3H, s) 6.81(1H, d, J=8.5 Hz), 6.97-7.02(3H, m),7.08(2H, d, J=8.8 Hz), 7.30(1H, m), 7.40(1H, dd, J=8.8, 1.9 Hz),7.45(1H, d, J=2.2 Hz), 8.70(1H, s), 8.78(1H, d, J=1.6 Hz), 11.76(1H, s).

Example 533 Preparation of the Compound of Compound No. 533

Using salicylic acid and 2,5-bis(trifluoromethyl)aniline as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 47.8%.

¹H-NMR(CD₃OD): δ 7.00-7.06(2H, m), 7.48(1H, dt, J=1.5, 7.5 Hz), 7.74(1H,d, J=8.4 Hz), 8.01-8.08(2H, m), 8.79(1H, s), 11.09(1H, s), 12.03(1H, s).

Example 534 Preparation of the Compound of Compound No. 534 (1)2-Amino-4-(2,4-dichlorophenyl)thiazole

Using 2′,4′-dichloroacetophenone and thiourea as the raw materials, thesame operation as the Example 395(1) gave the title compound.

Yield: 97.1%.

¹H-NMR(CDCl₃): δ 5.01(2H, s), 7.09(1H, s), 7.28(1H, dd, J=8.4, 2.1 Hz),7.45(1H, d, J=2.1 Hz), 7.82(1H, d, J=8.4 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(2,4-dichlorophenyl)thiazol-2-yl]benzamide(Compound No. 534)

Using 5-chlorosalicylic acid and 2-amino-4-(2,4-dichlorophenyl)thiazoleas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 8.0%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.50-7.55(2H, m),7.72-7.76(2H, m), 7.91(1H, d, J=8.4 Hz), 7.95(1H, d, J=2.4 Hz),11.87(1H, brs), 12.09(1H, brs).

Example 535 Preparation of the Compound of Compound No. 535

Using 3-isopropylsalicylic acid and 3,5-bis(trifluoromethyl)aniline asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 99.2%.

¹H-NMR(CDCl₃): δ 1.26(6H, d, J=6.9 Hz),3.44(1H, Hept, J=6.9 Hz),6.92(1H, t, J=7.8 Hz), 7.38(1H, dd, J=8.1, 1.2 Hz), 7.44(1H, d, J=7.5Hz), 7.69(1H, s), 8.13(3H, s), 11.88(1H, s).

Example 536 Preparation of the Compound of Compound No. 536

Bromine (14.4 μL, 0.28 mmol) and iron powder (1.7 mg, 0.03 mmol) wereadded to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-isopropylbenzamide(Compound No. 535; 100 mg, 0.26 mmol) in carbon tetrachloride (5 mL)under argon atmosphere, and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was diluted with ethyl acetate. Theethyl acetate layer was washed with water and brine, and dried overanhydrous magnesium sulfate. The residue obtained by evaporation of thesolvent under reduced pressure was crystallized from n-hexane/ethylacetate to give the title compound (110 mg, 91.5%) as a white solid.

¹H-NMR(CDCl₃): δ 1.25(6H, d, J=6.9 Hz), 3.39(1H, Hept, J=6.9 Hz),7.49-7.51(2H, m), 7.71(1H, brs), 8.11-8.14(3H, m), 11.81(1H, brs).

Example 537 Preparation of the Compound of Compound No. 537

N-Bromosuccinimide (88.2 mg, 0.50 mmol) was added to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-methylbenzamide (CompoundNo. 328; 150 mg, 0.41 mmol) in a mixed solvent of methanol/water (3:1; 5mL), and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was diluted with ethyl acetate. The ethyl acetate layerwas washed with 10% aqueous sodium thiosulfate, water and brine, anddried over anhydrous magnesium sulfate. The residue obtained byevaporation under reduced pressure was purified by column chromatographyon silica gel(n-hexane:ethyl acetate=5:1) to give the title compound(167 mg, 91.5%) as a white powder.

¹H-NMR(CDCl₃): δ 2.28(3H, s), 7.47(1H, s), 7.50(1H, d, J=2.4 Hz),7.71(1H, s), 8.08(1H, brs), 8.13(2H, s), 11.71(1H, s).

Example 538 Preparation of the Compound of Compound No. 538 (1)1-(3-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole

A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3 mg, 2mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2 mmol),concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL) was refluedfor 2 hours. After the reaction mixture was cooled to room temperature,it was poured into water and extracted with ethyl acetate. The ethylacetate layer was washed with water and brine, and dried over anhydroussodium sulfate. The residue obtained by evaporation under reducedpressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=4:1→3:1) to give the title compound (631.5mg, 94.7%) as a light yellowish white powder.

¹H-NMR(CDCl₃): δ 6.80(1H, s), 7.23-7.26(2H, m), 7.35-7.45(3H, m),7.54(1H, t, J=8.4 Hz), 7.63(1H, ddd, J=8.1, 1.8, 1.2 Hz), 8.19-8.25(2H,m).

(2) 1-(3-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole

Acetic acid (3 mL) and ethanol (2 mL) were added to1-(3-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole (0.59g, 1.77mmol) and 5% palladium on carbon (0.06g), and the mixture washydrogenated at room temperature for 2 hours under hydrogen atmosphere.After the insoluble matter was filtered off, the residue obtained byevaporation under reduced pressure was purified by column chromatographyon silica gel(n-hexane:ethyl acetate=2:1) to give the title compound(491.1 mg, 91.4%) as a white solid.

¹H-NMR(CDCl₃): δ 3.78(2H, s), 6.54(1H, ddd, J=7.8, 1.8, 0.6 Hz),6.65(1H, ddd, J=8.4, 2.4, 0.9 Hz), 6.73-6.75(2H, m), 7.07(1H, t, J=8.1Hz), 7.24-7.36(5H, m).

(3)5-Chloro-2-hydroxy-N-{3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-benzamide(Compound No. 538)

Using 5-chlorosalicylic acid and1-(3-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 74.4%.

¹H-NMR(CDCl₃): δ 6.77(1H, s), 6.97-7.03(2H, m), 7.27-7.45(8H, m),7.65(1H, ddd, J=8.4, 2.1, 0.9 Hz), 7.74(1H, t, J=2.1 Hz), 7.93(1H, s),11.63(1H, s).

Example 539 Preparation of the Compound of Compound No. 539 (1)5-(tert-Butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole

Using 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione and4-nitrophenylhydrazine hydrochloride as the raw materials, the sameoperation as the Example 538(1) gave the title compound.

Yield: 94.7%.

¹H-NMR(CDCl₃): δ 1.23(9H, s), 6.51(1H, s), 7.62(2H, d, J=9.0 Hz),8.37(2H, d, J=9.0 Hz).

(2) 1-(4-Aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole

Using 5-(tert-butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole asthe raw material, the same operation as the Example 538(2) gave thetitle compound.

Yield: 98.9%.

¹H-NMR(CDCl₃): δ 1.20(9H, s), 4.00(2H, br), 6.40(1H, s), 6.69(2H, d,J=8.7 Hz), 7.14(2H, d, J=9.0 Hz).

(3)N-{4-[5-(tert-butyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxy-benzamide(Compound No. 539)

Using 5-chlorosalicylic acid and1-(5-aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 57.6%.

¹H-NMR(CDCl₃): δ 1.23(9H, s), 6.47(1H, s), 7.00(1H, d, J=9.0 Hz),7.40-7.44(3H, m), 7.57(1H, d, J=2.4 Hz), 7.72(2H, d, J=8.7 Hz), 8.15(1H,s), 11.58(1H, s).

Example 540 Preparation of the Compound of Compound No. 540

Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-phenylbenzamide(Compound No. 527), the same operation as the Example 537 gave the titlecompound.

Yield: 67.5%.

¹H-NMR(DMSO-d₆): δ 7.36-7.50(3H, m), 7.55-7.59(2H, m), 7.71(1H, d, J=2.1Hz), 7.93(1H, brs), 8.28(1H, d, J=2.1 Hz), 8.45(2H, s), 11.06(1H, brs),12.16(1H, brs).

Example 541 Preparation of the Compound of Compound No. 541 (1)2-Amino-4-(3,4-dichlorophenyl)thiazole

Using 3′,4′-dichloroacetophenone and thiourea as the raw materials, thesame operation as the Example 395(1) gave the title compound.

Yield: 77.8%.

¹H-NMR(DMSO-d₆): δ 7.17(2H, s), 7.24(1H, s), 7.62(1H, d, J=8.4 Hz),7.78(1H, dd, J=8.7, 2.7 Hz), 8.22(1H, d, J=2.4 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(3,4-dichlorophenyl)thiazol-2-yl]benzamide(Compound No. 541)

Using 5-chlorosalicylic acid and 2-amino-4-(3,4-dichlorophenyl)thiazoleas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 15.1%.

¹H-NMR(DMSO-d₆): δ 7.08(1H, d, J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz),7.71(1H, d, J=8.4 Hz), 7.91(1H, d, J=1.8 Hz), 7.94(1H, s), 8.18(1H, d,J=1.5 Hz), 12.09(2H, bs).

Example 542 Preparation of the Compound of Compound No. 542 (1)2-Amino-4-[4-(trifluoromethyl)phenyl]thiazole

Using 4′-(trifluoromethyl)acetophenone and thiourea as the rawmaterials, the same operation as the Example 395(1) gave the titlecompound.

Yield: 77.5%.

¹H-NMR(DMSO-d₆): δ 7.18(2H, s), 7.26(1H, s), 7.72(2H, d, J=8.4 Hz),8.00(2H, d, J=8.1 Hz).

(2)5-Chloro-2-hydroxy-N-{4-[4-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 542)

Using 5-chlorosalicylic acid and2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 16.0%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=9.0 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.81(2H, d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 7.98(1H, s), 8.16(2H, d,J=8.1 Hz), 11.91(1H, bs), 12.13(1H, bs).

Example 543 Preparation of the Compound of Compound No. 543 (1)2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl)-5-chlorobenzamide

Using 2-acetoxy-5-chlorobenzoic acid and1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials,the same operation as the Example 24 gave the title compound.

Yield: 77.8%.

¹H-NMR(CDCl₃): δ 2.36(3H, s), 7.78(1H, s), 7.14(1H, d, J=8.7 Hz),7.48-7.51(3H, m), 7.77(2H, d, J=9.0 Hz), 7.83(1H, d, J=2.7 Hz), 8.25(1H,s).

[1-(4-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole: Refer to “Journalof Medicinal Chemistry”, 2000, Vol. 43, No. 16, p. 2975-2981.]

(2)N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxybenzamide(Compound No. 543)

Using2-acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamideas the raw material, the same operation as the Example 2(2) gave thetitle compound.

Yield: 73.1%.

¹H-NMR(DMSO-d₆): o 7.04(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),7.63(2H, d, J=8.7 Hz), 7.84(1H, s), 7.89(1H, d, J=3.0 Hz), 7.94(2H, d,J=9.0 Hz), 10.65(1H, s), 11.58(1H, s).

Example 544 Preparation of the Compound of Compound No. 544 (1)3,5-Bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole

Using hexafluoroacetylacetone and 3-nitrophenylhydrazine hydrochlorideas the raw materials, the same operation as the Example 538(1) gave thetitle compound.

Yield: 94.0%.

¹H-NMR(CDCl₃): δ 7.16(1H, s), 7.77(1H, dd, J=8.7, 8.1 Hz), 7.88-7.91(1H,m), 8.42-8.45(2H, m).

(2) 1-(3-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole

Using 3,5-bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole as the rawmaterial, the same operation as the Example 538(2) gave the titlecompound.

Yield: 73.1%.

¹H-NMR(CDCl₃): δ 3.89(2H, s), 6.77-6.87(3H, m), 7.04(1H, s), 7.26(1H, t,J=8.7 Hz).

(3)2-Acetoxy-N-{3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamide

Using 2-acetoxy-5-chlorobenzoic acid and1-(3-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials,the same operation as the Example 24 gave the title compound.

Yield: 84.4%.

¹H-NMR(CDCl₃): δ 2.33(3H, s), 7.09(1H, s),7.11(1H, d, J=9.0 Hz),7.30(1H, d, J=7.8 Hz), 7.45-7.52(2H, m), 7.67(1H, d, J=8.4 Hz), 7.78(1H,d, J=2.4 Hz), 7.95(1H, s), 8.29(1H, s).

(4)N-{3-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxybenzamide(Compound No. 544)

Using2-acetoxy-N-{3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenzamideas the raw material, the same operation as the Example 2(2) gave thetitle compound.

Yield: 69.9%.

¹H-NMR(CDCl₃): δ 7.01(1H, d, J=8.7 Hz), 7.10(1H, s), 7.34-7.37(1H, m),7.42(1H, dd, J=8.7, 2.4 Hz), 7.50(1H, d, J=2.4 Hz), 7.56(1H, t, J=8.1Hz), 7.69-7.73(1H, m), 7.95-7.98(2H, m), 11.57(1H, s).

Example 545 Preparation of the Compound of Compound No. 545 (1) Methyl2-methoxy-4-phenylbenzoate

Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added toa solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol),phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7g, 8.2mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and themixture was stirred at 120° C. for 8 hours. After the reaction mixturewas cooled to room temperature, it was diluted with ethyl acetate. Theethyl acetate layer was washed successively with water and brine, anddried over anhydrous sodium sulfate. The residue obtained by evaporationof the solvent under reduced pressure was purified by columnchromatography on silica gel(n-hexane:ethyl acetate=10:1) to give thetitle compound (410 mg, 41.2%) as a colourless oil.

¹H-NMR(CDCl₃): δ 3.91(3H, s), 3.98(3H, s), 7.17(1H, d, J=1.5 Hz),7.20(1H, dd, J=8.1, 1.5 Hz), 7.31-7.50(3H, m), 7.59-7.63(2H, m),7.89(1H, d, J=8.1 Hz).

(2) 2-Methoxy-4-phenylbenzoic acid

2N Aqueous sodium hydroxide (5 mL) was added to a solution of methyl2-methoxy-4-phenylbenzoate (410 mg, 1.69 mmol) in methanol (5 mL), andthe mixture was refluxed for 1 hour. After the reaction mixture wascooled to room temperature, the solvent was evaporated under reducedpressure. 2N hydrochloric acid was added to the obtained residue and theseparated crystal was filtered to give the title compound (371 mg,96.0%) as a crude product.

¹H-NMR(DMSO-d₆): δ 3.93(3H, s), 7.29(1H, dd, J=8.1, 1.5 Hz), 7.34(1H, d,J=1.5 Hz), 7.40-7.53(3H, m), 7.73-7.77(3H, m), 12.60(1H, s).

(3) N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide

Using 2-methoxy-4-phenylbenzoic acid and 3,5-bis(trifluoromethyl)anilineas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 97.5%.

¹H-NMR(CDCl₃): δ 4.19(3H, s), 7.25(1H, m), 7.38-7.53(4H, m),7.62-7.65(3H, m), 8.12(2H, s), 8.35(1H, d, J=8.1 Hz), 10.15(1H, brs).

(4) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-4-phenylbenzamide(Compound No. 545)

1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71 mmol) wasadded to a solution ofN-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (100 mg,0.24 mmol) in dichloromethane (5 mL), and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted with ethylacetate, washed with water and brine, and dried over anhydrous magnesiumsulfate. The residue obtained by evaporation of the solvent underreduced pressure was purified by column chromatography on silicagel(n-hexane:ethyl acetate=5:1) to give the title compound (69.3 mg,71.6%) as a white powder.

¹H-NMR(DMSO-d₆): δ 7.20(1H, dd, J=8.4.1.8 Hz), 7.30(1H, d, J=1.8 Hz),7.39-7.51(3H, m), 7.60-7.64(3H, m), 7.70(1H, brs), 8.15(2H, s), 8.19(1H,brs), 11.59(1H, s).

Example 546 Preparation of the Compound of Compound No. 546 (1)2-Amino-4-(2,5-difluorophenyl)thiazole

Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, thesame operation as the Example 395(1) gave the title compound.

Yield: 77.8%.

¹H-NMR(DMSO-d₆): δ 7.45(1H, d, J=2.7 Hz), 7.11-7.17(1H, m), 7.19(2H, s),7.28-7.36(1H, m), 7.65-7.71(1H, m).

(2) 5-Chloro-2-hydroxy-N-[4-(2,5-difluorophenyl)thiazol-2-yl]benzamide(Compound No. 546)

Using 5-chlorosalicylic acid and 2-amino-4-(2,5-difluorophenyl)thiazoleas the raw materials, the same operation as the Example 16 gave thetitle compound.

Yield: 36.5%.

¹H-NMR(DMSO-d₆): δ 7.09(1H, d, J=8.7 Hz), 7.22-7.30(1H, m), 7.37(1H, m),7.53(1H, dd, J=8.7, 3.0 Hz), 7.72(1H, d, J=2.4 Hz), 7.77-7.84(1H, m),7.94(1H, d, J=3.0 Hz), 11.89(1H, bs), 12.12(1H, bs).

Example 547 Preparation of the Compound of Compound No. 547 (1)2-Acetoxy-4-chlorobenzoic acid

Using 4-chlorosalicylic acid, concentrated sulfuric acid and aceticanhydride as the raw materials, the same operation as the Example 34(1)gave the title compound.

Yield: 88.1%.

¹H-NMR(DMSO-d₆): δ 2.25(3H, s), 7.42(1H, d, J=1.8 Hz), 7.48(1H, dd,J=8.4, 2.4 Hz), 7.94(1H, d, J=8.1 Hz), 13.31(1H, s).

(2)2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorobenzamide

Using 2-acetoxy-4-chlorobenzoic acid and1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials,the same operation as the Example 24 gave the title compound.

Yield: 74.0%.

¹H-NMR(CDCl₃): δ 2.37(3H, s), 7.08(1H, s), 7.23(1H, d, J=1.8 Hz),7.37(1H, dd, J=8.1, 2.1 Hz), 7.50(2H, d, J=8.7 Hz), 7.77(2H, d, J=8.7Hz), 7.82(1H, d, J=8.1 Hz), 8.23(1H, s).

(3)N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chloro-2-hydroxybenzamide(Compound No. 547)

Using2-acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorobenzamideas the raw material, the same operation as the Example 2(2) gave thetitle compound.

Yield: 56.6%.

¹H-NMR(DMSO-d₆): δ 7.03-7.06(2H, m), 7.61(2H, d, J=8.7 Hz), 7.81(1H, s),7.89-7.95(3H, m), 10.62(1H, s), 11.82(1H, s).

Example 548 Preparation of the Compound of Compound No. 548 (1)1-(4-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole

Using 4,4,4-trifluoro-1-phenyl-1,3-butanedione and4-nitrophenylhydrazine hydrochloride as the raw materials, the sameoperation as the Example 538(1) gave the title compound.

Yield: 95.2%.

¹H-NMR(CDCl₃): δ 6.80(1H, s), 7.22-7.26(2H, m), 7.37-7.45(3H, m),7.51(2H, d, J=9.3 Hz), 8.22(2H, d, J=9.0 Hz).

(2) 1-(4-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole

Using 1-(4-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the rawmaterial, the same operation as the Example 538(2) gave the titlecompound.

Yield: 73.0%.

¹H-NMR(CDCl₃): δ 3.80(2H, s), 6.62(2H, d, J=8.7 Hz),6.72(1H, s),7.08(2H, d, J=8.7 Hz), 7.22-7.26(2H, m), 7.30-7.33(3H, m).

(3)5-Chloro-2-hydroxy-N-{4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-benzamide(Compound No. 548)

Using 5-chlorosalicylic acid and1-(4-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the rawmaterials, the same operation as the Example 16 gave the title compound.

Yield: 73.2%.

¹H-NMR(CDCl₃): δ 7.02(1H, d, J=8.7 Hz), 7.21(1H, s), 7.30-7.42(7H, m),7.47(1H, dd, J=8.7, 2.7 Hz), 7.79(2H, d, J=8.7 Hz), 7.89(1H, d, J=2.7Hz), 10.56(1H, s), 11.61(1H, s).

Example 549 Preparation of the Compound of Compound No. 549 (1)2-Amino-4-(4-methoxyphenyl)thiazole

Using 4′-methoxyacetophenone and thiourea as the raw materials, the sameoperation as the Example 395(1) gave the title compound.

Yield: 85.2%.

¹H-NMR(DMSO-d₆): δ 3.76(3H, s), 6.82(1H, s), 6.92(2H, d, J=9.0 Hz),7.01(2H, s), 7.72(2H, d, J=8.7 Hz).

(2) 5-Chloro-2-hydroxy-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzamide(Compound No. 549)

Using 5-chlorosalicylic acid and 2-amino-4-(4-methoxyphenyl)thiazole asthe raw materials, the same operation as the Example 16 gave the titlecompound.

Yield: 16.4%.

¹H-NMR(DMSO-d₆): δ 3.80(3H, s), 7.01(2H, d, J=9.0 Hz), 7.07(1H, d, J=8.7Hz), 7.50-7.55(2H, m), 7.86(2H, d, J=9.0 Hz), 7.96(1H, d, J=2.7 Hz),11.90(1H, bs), 12.04(1H, bs).

Example 550 Preparation of the Compound of Compound No. 550 (1)2-Amino-4-[3-(trifluoromethyl)phenyl]thiazole

Using 3′-(trifluoromethyl)acetophenone and thiourea as the rawmaterials, the same operation as the Example 395(1) gave the titlecompound.

Yield: 94.1%.

¹H-NMR(DMSO-d₆): δ 7.19(2H, s), 7.27(1H, s), 7.61(2H, dd, J=3.9, 1.5Hz), 8.07-8.13(2H, m).

(2)5-Chloro-2-hydroxy-N-{4-[3-(trifluoromethyl)phenyl]thiazol-2-yl}benzamide(Compound No. 550)

Using 5-chlorosalicylic acid and2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials, thesame operation as the Example 16 gave the title compound.

Yield: 31.0%.

¹H-NMR(DMSO-d₆): δ 7.13(1H, d, J=8.7 Hz), 7.53(1H, dd, J=9.0, 2.7 Hz),7.70(1H, d, J=2.4 Hz), 7.71(1H, d, J=1.2 Hz), 7.95(1H, d, J=2.7 Hz),8.00(1H, s), 8.24-8.27(2H, m), 12.16(2H, bs).

Example 551 Preparation of the Compound of Compound No. 551 (1)2-Amino-4-(2,3,4,5,6-pentafluorophenyl)thiazole

Using 2′,3′,4′,5′,6′-pentafluoroacetophenone and thiourea as the rawmaterials, the same operation as the Example 395(1) gave the titlecompound.

Yield: 86.7%.

¹H-NMR(CDCl₃): δ 5.19(2H, s), 6.83(1H, s).

(2)5-Chloro-2-hydroxy-N-[4-(2,3,4,5,6-pentafluorophenyl)thiazol-2-yl]benzamide(Compound No. 551)

Using 5-chlorosalicylic acid and2-amino-4-(2,3,4,5,6-pentafluorophenyl)-thiazole as the raw materials,the same operation as the Example 16 gave the title compound.

Yield: 23.8%.

¹H-NMR(DMSO-d₆): o 7.08(1H, d, J=8.7 Hz), 7.53(1H, dd, J=8.7, 2.7 Hz),7.73(1H, s), 7.93(1H, d, J=2.7 Hz), 11.85(1H, bs), 12.15(1H, bs).

Example 552 Preparation of the Compound of Compound No. 552

Iron (3 mg, 0.05 mmol) and bromine (129 μl, 2.5 mmol) were added to asolution of 2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide(Compound No. 533; 175 mg, 0.5 mmol) in carbon tetrachloride (5 mL), andthe mixture was stirred at 50° C. for 12 hours. After the reactionmixture was cooled to room temperature, it was washed with saturatedaqueous sodium hydrogen carbonate, water and brine, and dried overanhydrous magnesium sulfate. The residue obtained by evaporation of thesolvent under reduced pressure was purified by column chromatography onsilica gel(n-hexane:ethyl acetate=2:1) to give the title compound (184.2mg, 72.7%) as a white crystal.

¹H-NMR(DMSO-d₆): δ 7.92-7.98(1H, m), 8.06(1H, d, J=2.1 Hz), 8.09(1H, d,J=8.4 Hz), 8.22(1H, d, J=2.1 Hz), 8.27-8.32(1H, m), 11.31(1H, s).

Example 553 Preparation of the Compound of Compound No. 553

Using 2,3-dihydroxybenzaldehyde and3-[3,5-bis(trifluoromethyl)benzyl]-thiazolidine-2,4-dione(compound ofExample 319(1)) as the raw materials, the same operation as the Example319(2) gave the title compound.

Yield: 88.5%.

¹H-NMR(DMSO-d₆): δ 5.02(2H, s), 6.88(1H, d, J=7.8 Hz), 7.00-7.04(2H, m),7.79(1H, s), 8.03(2H, s), 8.07(1H, s), 9.49(1H, s), 9.91(1H, s).

Example 554 Preparation of the Compound of Compound No. 554

A mixture of 5-chlorosalicylaldehyde (157 mg, 1 mmol),2-amino-4-tert-amylphenyl phenyl ether (255 mg, 1 mmol) and ethanol (2mL) was stirred at room temperature for 18 hours. The residue obtainedby evaporation of the solvent under reduced pressure was purified bycolumn chromatography on silica gel(n-hexane:ethyl acetate=100:1) togive the title compound (57 mg, 14.4%) as a white solid.

¹H-NMR(CDCl₃):δ 0.66(3H, t, J=7.5 Hz), 1.26(6H, s), 1.61(2H, q, J=7.5Hz), 6.88-6.94(3H, m), 7.04(1H, dd, J=8.0, 1.6 Hz), 7.15-7.32(7H, m),8.61(1H, s), 13.20(1H, s).

Example 555 Preparation of the Compound of Compound No. 555

A mixture of4-chloro-2-({[2-phenoxy-5-(tert-amyl)phenyl]imino}-methyl)phenol(Compound No. 554; 13 mg, 0.03 mmol), sodium borohydride (1.2 mg, 0.03mmol) and methanol (1 mL) was stirred at room temperature for 5 minutes.The residue obtained by evaporation of the solvent under reducedpressure was purified by thin layer chromatography on silicagel(n-hexane:ethyl acetate=5:1) to give the title compound (13 mg, 100%)as a colourless oil.

¹H-NMR(CDCl₃): δ 0.69(3H, t, J=7.6 Hz), 1.28(6H, s), 1.63(2H, q, J=7.6Hz), 4.41(2H, s), 6.78(1H, m), 6.93-6.83(5H, m), 7.03(1H, m), 7.15(2H,m), 7.28(3H, m).

Test Example 1 Proliferation Inhibitory Test of Mast Cell understimulation by SCF and IL-3

Bone marrow-derived cultured mast cells (10⁵ cells/ml) of NC/Nga mousewere cultured with rmIL-3 (100 U/ml) and SCF (100 ng/ml) in the presenceor absence of a test drug in α-Modified Eagle's Medium containing 10% ofbovine fetal serum without phenol red, and then stained with trypanblue, and the number of living cells was counted. The results are shownin the following table. Number of Cell (×10⁵/ml) Compound Culture TimeNumber Concentration(μM) 0 hr 24 hr 48 hr 72 hr — 0 1.0 1.3 1.7 2.6 50 11.0 0.86 0.84 1.16 5 1.0 0.7 0.52 0.22

Test Example 2 Degranulation Inhibitory Test of Mast Cell

Anti DNP IgE was added to mouse bone marrow-derived cultured mast cells(BMCMC) which were treated beforehand with anti DNP IgE for 4 days forexpression of IgE receptor. The cells were cultured for 3 days, andtreated for 1 hour with or without the addition of a test substance.Then, the medium was changed to a -Modified Eagle's Medium containing10% of bovine fetal serum without phenol red. After cultivation for 60minutes with rmIL-3 (100 U/ml) and DNP-BSA (50ng/ml) in the presence orabsence of the test substance, the concentrations of β-hexosaminidase inthe culture medium and in the cells were determined, and the progress ofdegranulation was measured from a ratio of the amounts. The inhibitoryratio of the degranulation by the drug was calculated when degranulationin the absence of the test substance was taken as 100%, anddegranulation in the presence of anti DNP-IgE only and in the absence ofthe test substance was taken as 0%. The results are shown in thefollowing table. Inhibitory Ration of Degranulation(%) Compound Numberat 10 μM Drug Concentration 50 >99 56 92 63 62 73 91 100 83 101 90 11393 114 88 122 91 163 88 195 72

Test Example 3 IgE Production Inhibitory Test of Spleen B Cell

B cells isolated from mouse spleen were cultured with 200 U/ml of rmIL-4and 100 ng/ml of soluble mCD40 ligand in the presence or absence of atest drug in PRMI 1640 medium containing 10% of bovine fetal serum for 9days, and the amount of IgE in the culture medium was measured by ELISAmethod. The results are shown in the following table Amount ofIgE(ng/ml) Concentration(μM) Compound Number 0 0.1 1.0 — 45.6 — — 50 —24 NDND = not detected

Test Example 4 Immediate Type Allergy Reaction Inhibitory Test (EarSwelling Test)

To NC/Nga mouse sensitized by an intravenous administration of antiDNP-IgE, a diluent with a test compound for the drug administered groupor that without a test drug for the control group was intraperitoneallyadministered. Two hours after the administration, picryl chloridedissolved in olive oil was applied to auricle to induce immediateallergy, and then swelling of the auricle was measured with passage oftime for comparison of the drug administered group and the controlgroup. The results of Compound 50 (dose: 15 mg/kg) are shown in FIG. 1.

Test Example 5 Dermatitis Inhibitory Test by Atopic Dermatitis ModelUsing NC/Nga Mouse

To the conventional NC/Nga mouse with the onset of severe dermatitis, anointment containing 1% of a test substance for the drug treated group ora base material of the ointment for the control group was applied once aday, and clinical symptoms were recorded as scores with passage of day.Furthermore, the amounts of IgE in blood before and after the test weremeasured by ELISA. The results for Compound 50 are shown in FIG. 2.

Test Example 6 Proliferation Inhibitory Test of Fibrosarcoma (HT-1080)Under PDGF Stimulation

HT-1080 cells were cultured for 2 hours in EMEM medium containing 1% ofFBS and NEAA in the presence or absence of a test substance. PDGF wasadded and the cells were cultured for 48 hours, and the proliferation ofthe cells was measured by MTT assay. The results are shown in thefollowing table. Inhibitory Ratio of Proliferation(%) Compound DrugConcentration Number 500 nM 250 nM 50 96.6 65.4 51 97.6 62.4 67 70.938.5 73 84.9 52.0 63 77.9 48.3 114 95.7 48.8 163 80.8 16.9 71 83.1 57.956 96.9 37.5 98 59.4 26.4 196 80.2 47.3 122 51.1 32.9 195 81.7 44.7 19924.2 26.2 201 76.2 60.3 532 91.8 42.2 552 19.4 24.0 101 80.0 53.2

INDUSTRIAL APPLICABILITY

The medicaments of the present invention are useful for the preventiveand/or therapeutic treatment of allergic diseases and/or endometriosisand/or hysteromyoma.

1. A medicament for the preventive and/or therapeutic treatment of anallergic disease and/or endometriosis and/or hysteromyoma, whichcomprises as an active ingredient a substance selected from the groupconsisting of a compound represented by the following general formula(I) and a pharmacologically acceptable salt thereof, and a hydratethereof and a solvate thereof:

wherein X represents a connecting group whose number of atoms in themain chain is 2 to 5 (said connecting group may be substituted), Arepresents hydrogen atom or acetyl group, E represents an aryl groupwhich may be substituted or a heteroaryl group which may be substituted,ring Z represents an arene which may have one or more substituents inaddition to the group represented by formula —O-A wherein A has the samemeaning as that defined above and the group represented by formula —X-Ewherein each of X and E has the same meaning as that defined above, or aheteroarene which may have one or more substituents in addition to thegroup represented by formula —O-A wherein A has the same meaning as thatdefined above and the group represented by formula —X-E wherein each ofX and E has the same meaning as that defined above.
 2. The medicamentaccording to claim 1, wherein X is a group selected from the followingconnecting group α (said group may be substituted): [Connecting Group α]The groups of the following formulas:

wherein a bond at the left end binds to ring Z and a bond at the rightend binds to E.
 3. The medicament according to claim 2, wherein X is agroup represented by the following formula (said group may besubstituted):

wherein a bond at the left end binds to ring Z and a bond at the rightend binds to E.
 4. The medicament according to claim 1, wherein A is ahydrogen atom.
 5. The medicament according to claim 1, wherein ring Z isa C₆ to C₁₀ arene which may have one or more substituents in addition tothe group represented by formula —O-A wherein A has the same meaning asthat defined in the general formula (I) and the group represented byformula —X-E wherein each of X and E has the same meaning as thatdefined in the general formula (I), or a 5 to 1 3-membered heteroarenewhich may have one or more substituents in addition to the grouprepresented by formula —O-A wherein A has the same meaning as thatdefined in the general formula (I) and the group represented by formula—X-E wherein each of X and E has the same meaning as that defined in thegeneral formula (I).
 6. The medicament according to claim 5, whereinring Z is a ring selected from the following ring group β: [Ring Groupβ] benzene ring, naphthalene ring, thiophene ring, pyridine ring, indolering, quinoxaline ring, and carbazole ring wherein said ring may haveone or more substituents in addition to the group represented by formula—O-A wherein A has the same meaning as that defined in the generalformula (I) and the group represented by formula —X-E wherein each of Xand E has the same meaning as that defined in the general formula (I).7. The medicament according to clam 6, wherein ring Z is a benzene ringwhich may have one or more substituents in addition to the grouprepresented by formula —O-A wherein A has the same meaning as thatdefined in the general formula (I) and the group represented by formula—X-E wherein each of X and E has the same meaning as that defined in thegeneral formula (I).
 8. The medicament according to claim 7, whereinring Z is a benzene ring which is substituted with halogen atom(s) inaddition to the group represented by formula —O-A wherein A has the samemeaning as that defined in the general formula (I) and the grouprepresented by formula —X-E wherein each of X and E has the same meaningas that defined in the general formula (I).
 9. The medicament accordingto claim 6, wherein ring Z is a naphthalene ring which may have one ormore substituents in addition to the group represented by formula —O-Awherein A has the same meaning as that defined in the general formula(I) and the group represented by formula —X-E wherein each of X and Ehas the same meaning as that defined in the general formula (I).
 10. Themedicament according to claim 1, wherein E is a C₆ to C₁₀ aryl groupwhich may be substituted or a 5 to 13-membered heteroaryl group whichmay be substituted.
 11. The medicament according to claim 10, wherein Eis a phenyl group which may be substituted.
 12. The medicament accordingto claim 11, wherein E is 3,5-bis(trifluoromethyl)phenyl group.
 13. Themedicament according to claim 10, wherein E is a 5-membered heteroarylgroup which may be substituted.
 14. The medicament according to claim 1,having inhibitory activity against production of IgE, inhibitoryactivity against degranulation from activated a mast cell, and/orinhibitory activity against proliferation of a mast cell.
 15. A compoundrepresented by the general formula (I-1) or a salt thereof, or a hydratethereof or a solvate thereof:

wherein Z¹ represents 2-hydroxyphenyl group which may be substituted inthe 5-position or 2-acetoxyphenyl group which may be substituted in the5-position, and E¹ represents a phenyl group which may be substituted.16. The compound according to claim 15 or a salt thereof, or a hydratethereof or a solvate thereof, wherein E¹ is2,5-bis(trifluoromethyl)phenyl group or 3,5-bis(trifluoromethyl)phenylgroup, provided that the following compounds are excluded:N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide, andN-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide.
 17. Thecompound according to claim 16 or a salt thereof, or a hydrate thereofor a solvate thereof, wherein Z¹ is 2-hydroxyphenyl group which issubstituted with a halogen atom in the 5-position or 2-acetoxyphenylgroup which is substituted with a halogen atom in the 5-position.
 18. Acompound represented by the general formula (I-2) or a salt thereof, ora hydrate thereof or a solvate thereof:

wherein Z² represents 2-hydroxyphenyl group which may be substituted inthe 5-position or 2-acetoxyphenyl group which may be substituted in the5-position, E² represents a 2,5-di-substituted phenyl group wherein oneof said substituents is trifluoromethyl group or a 3,5-di-substitutedphenyl group wherein one of said substituents is trifluoromethyl group,provided that the following compounds are excluded:5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]benzamide,5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide,5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,5-chloro-2-hydoxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide,and5-chloro-2-hydoxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.19. The compound according to claim 18 or a salt thereof, or a hydratethereof or a solvate thereof, wherein Z² is 2-hydroxyphenyl group whichis substituted with a halogen atom in the 5-position or 2-acetoxyphenylgroup which is substituted with a halogen atom in the 5-position. 20.The compound represented by the general formula (I-3) or a salt thereof,or a hydrate thereof or a solvate thereof:

wherein Z³ represents 2-hydroxyphenyl group which may be substituted inthe 5-position or 2-acetoxyphenyl group which may be substituted in the5-position, E³ represents a group represented by the following formula:

wherein one of R^(3e2) and R^(3e3) represents hydrogen atom and theother represents a hydrocarbon group which may be substituted orhydroxyl group which may be substituted, and R^(3e5) represents a C₂ toC₆ hydrocarbon group which may be substituted.
 21. The compoundaccording to claim 20 or a salt thereof, or a hydrate thereof or asolvate thereof, wherein Z³ is 2-hydroxyphenyl group which issubstituted with a halogen atom in the 5-position or 2-acetoxyphenylgroup which is substituted with a halogen atom in the 5-position.
 22. Acompound represented by the general formula (I-4) or a salt thereof, ora hydrate thereof or a solvate thereof:

wherein Z⁴ represents 2-hydroxyphenyl group which may be substituted inthe 5-position or 2-acetoxyphenyl group which may be substituted in the5-position, E⁴ represents a group represented by the following formula:

wherein R^(4e4) represents a hydrocarbon group which may be substituted,R^(4e5) represents a halogen atom, cyano group, an acyl group which maybe substituted, or a heterocyclic group which may be substituted. 23.The compound according to claim 22 or a salt thereof, or a hydratethereof or a solvate thereof, wherein Z⁴ is 2-hydroxyphenyl group whichis substituted with a halogen atom in the 5-position or 2-acetoxyphenylgroup which is substituted with a halogen atom in the 5-position.